Conditions: Cachexia; Cancer Non Small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 318
Healthy volunteers: no

Brief summary:
The goal of this clinical trial was to compare the efficacy and safety of anamorelin HCl (the investigational drug) to that of placebo (tablet with no drug) in patients with advanced non-small cell lung cancer and cachexia (cancer-related weight loss). The main question it aimed to answer was as follows: Do patients who receive anamorelin HCl gain more body weight and show more improvement in anorexia symptoms than those who receive placebo.

Approximately 316 patients were to be enrolled in the study. Of these patients, an equal number were to be assigned to each treatment group (anamorelin HCl or placebo). Participants were to take their assigned study drug by mouth once daily for a total of 24 weeks. During this treatment period, the patients were to visit the clinical study site every 3 weeks for health and other study-related assessments. Two weeks after the last treatment, patients were to receive a follow-up phone call.

Detailed description:
The study was a multicenter, randomized, double-blind, parallel-group, placebo controlled study to evaluate the efficacy and safety of anamorelin HCl. It was planned that approximately 316 patients with advanced NSCLC with cachexia were to be randomized 1:1 to anamorelin HCl 100 mg or placebo (158 patients per treatment group). The study treatment was to be taken orally once daily for a total of 24 weeks. Patients were instructed to take the study drug at least 1 hour before their first meal of the day.

Central randomization was stratified by line of systemic anti-cancer treatment (first line vs second line vs third line or higher), by type of anti-cancer therapy (immunotherapy vs non-immunotherapy), and by baseline score of the 5-item Anorexia Symptom Subscale (5-IASS) (≤10 vs \>10).

Patients who had never received anti-cancer treatment prior to entering the study but who met all eligibility criteria were eligible to enter the study and were assigned to receive first line treatment in the Interactive Web Response System (IWRS).

Patients were to visit the site every 3 weeks for the study Treatment Period of 24 weeks. A follow-up telephone visit was to be scheduled at Week 26. Thus, patients were enrolled in the study for a maximum duration of 27 weeks (including a 1-week Screening Period, a 24-week Treatment Period, and a 2-week Follow-up Period). Each patient was scheduled to have a total of 10 planned visits plus 1 telephone contact for the Follow-up Visit.

Arms:
arm 1: 100 mg anamorelin HCl (administered as film-coated tablets in fasted condition) was to be taken orally once daily for a total of 24 weeks arm 2: Placebo (administered as matching placebo tablets in fasted condition) was to be taken orally once daily for a total of 24 weeks

Interventions: intervention 1: Anamorelin Hydrochloride intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: 100 mg anamorelin HCl (administered as 100 mg tablets in the fasted condition) intervention 2: Placebo (administered as matching placebo tablets in the fasted condition)

Protocol document:
Prot_000.pdf: 
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CONFIDENTIAL 
 
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-17-20 
Protocol Version 
Final (v5.0) 
Protocol Date 
EudraCT No. 
13 Jul 2022 
2018-002926-22 
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) 
 
 
 
 
 
(Date
 
 
Drug Safety Manager, Regulatory Affairs & Drug Safety:  
 
________________________________________ _______
(Signature) 
 
 
 
 
 
(Date) 
 
 
Medical Writer, Clinical Research & Development: 
 
________________________________________ __
(Signature) 
 
 
 
 
 
(D
 
 
 




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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-17-20  
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 .................................................................................................23 
LIST OF ABBREVIATIONS .........................................................................................27 
1 
INTRODUCTION AND RATIONALE .................................................................30 
1.1 
Background Information ....................................................................................30 
1.2 
Anamorelin: preclinical and clinical data..........................................................31 
1.2.1 
Preclinical Data ..............................................................................................31 
1.2.2 
Phase 1 Clinical Data .....................................................................................32 
1.3 
Other Clinical Data ..............................................................................................32 
1.4 
Study Rationale ....................................................................................................33 
1.4.1 
Rationale for Study Population ....................................................................33 
1.4.2 
Rationale for Study Protocol and Design.....................................................34 
1.4.3 
Rationale for Selected Dose Range ...............................................................34 
1.5 
Rationale for protocol amendment.....................................................................34 
2 
STUDY OBJECTIVES ............................................................................................35 
2.1 
Primary Objective ................................................................................................35 
2.1.1 
Estimand .........................................................................................................35 
2.2 
Secondary Objectives...........................................................................................35 
3 
STUDY ENDPOINTS ..............................................................................................36 
3.1 
Efficacy Endpoints ...............................................................................................36 
3.1.1 
Primary Efficacy Endpoint ...........................................................................36 
3.1.2 
Secondary Efficacy Endpoints ......................................................................36 
3.1.3 
Exploratory Efficacy Endpoints ...................................................................36 
3.2 
Safety Assessments ...............................................................................................37 
4 
STUDY PLAN ...........................................................................................................38 
4.1 
Study Design .........................................................................................................38 
4.2 
Study Duration .....................................................................................................38 
4.3 
Study population ..................................................................................................38 
4.3.1 
Number of Subjects........................................................................................38 
4.3.2 
Inclusion Criteria ...........................................................................................38 
4.3.3 
Exclusion Criteria ..........................................................................................40 
5 
STUDY DRUG MANAGEMENT ...........................................................................42 
5.1 
Description of Study Treatments ........................................................................42 
5.2 
Treatment Groups ...............................................................................................42 
5.3 
Dose and Administration .....................................................................................42 
5.4 
Packaging, Labelling and Shipment ...................................................................42 
5.5 
Storage ..................................................................................................................42 
5.6 
Drug Depots ..........................................................................................................43 
5.7 
Accountability ......................................................................................................43 
5.8 
Administration of Study Treatment ...................................................................43 
5.9 
Blinding .................................................................................................................44 


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5.10 
Treatment Assignment and Randomization - Use of IWRS ............................44 
5.11 
Management of Treatment Overdosage ............................................................44 
5.12 
Occupational safety ..............................................................................................45 
5.13 
Prior and concomitant medications ...................................................................45 
5.13.1 
Use of corticosteroids .....................................................................................45 
5.13.2 
Prohibited Medications .................................................................................45 
5.13.3 
Concurrent NSCLC Treatment ....................................................................46 
5.13.4 
Use of contraceptive measures ......................................................................47 
5.14 
Rescue Medication ...............................................................................................47 
5.15 
Treatment Compliance ........................................................................................47 
6 
STUDY CONDUCT..................................................................................................48 
6.1 
Study Procedures by Time Point ........................................................................48 
6.1.1 
Visit 1 (Screening, Day -7 to Day -1) ............................................................48 
6.1.2 
Visit 2 (Randomization/Treatment Period, Day 1): Week 1 ......................49 
6.1.3 
Visit 3 (Day 22+3): Week 3 ............................................................................50 
6.1.4 
Visit 4 (Day 43+3days): Week 6 ....................................................................51 
6.1.5 
Visit 5 (Day 64+3 days): Week 9 ...................................................................52 
6.1.6 
Visit 6 (Day 85+3): Week 12 ..........................................................................53 
6.1.7 
Visit 7 (Day 106+3): Week 15 ........................................................................54 
6.1.8 
Visit 8 (Day 127+3) – Week 18 ......................................................................55 
6.1.9 
Visit 9 (Day 148+3): Week 21 ........................................................................56 
6.1.10 
Visit 10 (Day 169+3): Week 24 ......................................................................57 
6.1.11 
Visit 11 (Follow-up visit): Week 26 ..............................................................58 
6.2 
Definition of study Completion ...........................................................................58 
6.3 
Premature Discontinuation of Study Drug ........................................................58 
6.4 
Diet and Lifestyle .................................................................................................59 
7 
METHODS OF ASSESSMENT ..............................................................................60 
7.1 
Efficacy Assessments ...........................................................................................60 
7.1.1 
Assessment of Body Weight ..........................................................................60 
7.1.2 
Assessment of anorexia symptoms and other patient reported 
outcomes..........................................................................................................61 
7.1.3 
Patient Reported Outcome ............................................................................61 
7.2 
Safety Assessments ...............................................................................................63 
7.2.1 
Demographic/Medical History ......................................................................63 
7.2.2 
Physical examination .....................................................................................63 
7.2.3 
Vital signs ........................................................................................................64 
7.2.4 
Height and BMI..............................................................................................64 
7.2.5 
12-lead ECG ...................................................................................................64 
7.2.6 
Clinical Laboratory Tests..............................................................................64 
7.2.7 
CT scan for Tumor Assessment ....................................................................65 
8 
ADVERSE EVENTS ................................................................................................66 
8.1 
Definition of Adverse Events...............................................................................66 
8.1.1 
Classification of Adverse Events...................................................................67 
8.1.2 
Reporting Adverse Events .............................................................................69 


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8.1.3 
Reporting Serious Adverse Events ...............................................................70 
8.1.4 
Pregnancy Report ..........................................................................................71 
9 
STATISTICS .............................................................................................................72 
9.1 
Stratification factors ............................................................................................72 
9.2 
Sample Size Determination .................................................................................72 
9.3 
Definition of Study Populations for Analysis (Analysis Set) ............................73 
9.4 
Statistical Analysis ...............................................................................................73 
9.4.1 
Missing Data ...................................................................................................73 
9.4.2 
Multiplicity .....................................................................................................74 
9.4.3 
Subgroups .......................................................................................................75 
9.4.4 
Analysis of Demographics, Baseline Variables and Disease 
Characteristics................................................................................................75 
9.4.5 
Efficacy Analysis ............................................................................................75 
9.4.6 
Safety Analysis ...............................................................................................80 
9.4.7 
Determination of the responder threshold in the 5-item Anorexia 
Symptom Subscale .........................................................................................81 
9.4.8 
Determination of the clinically meaningful responder threshold in 
weight change .................................................................................................82 
9.5 
Interim Analysis ...................................................................................................83 
10 ETHICAL AND REGULATORY ASPECTS........................................................84 
10.1 
Ethical Considerations.........................................................................................84 
10.1.1 
Laws and Regulations ....................................................................................84 
10.1.2 
Patient’s information sheet and informed consent form ............................84 
10.1.3 
Protocol amendments ....................................................................................84 
10.1.4 
Protocol deviations .........................................................................................85 
10.1.5 
Data collection ................................................................................................85 
10.1.6 
Monitoring and Quality Assurance ..............................................................86 
10.1.7 
Study Documentation and Records retention .............................................86 
10.1.8 
Confidentiality ................................................................................................87 
10.1.9 
Publication policy ...........................................................................................87 
10.1.10 
Insurance ........................................................................................................88 
11 REFERENCES .........................................................................................................89 
12 APPENDICES ...........................................................................................................93 
APPENDIX 1: 
EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE SCALE ......................................................................................94 
APPENDIX 2: 
BODY WEIGHT MEASUREMENTS-STUDY SPECIFIC 
PROCEDURES .........................................................................................................95 
APPENDIX 3: 
CYP3A4 INHIBITORS AND INDUCERS ......................................96 
APPENDIX 4: 
FACIT MEASUREMENTS ..............................................................97 
APPENDIX 5: 
SCORING GUIDELINES ...............................................................102 
APPENDIX 6: 
PATIENT GLOBAL IMPRESSION OF SEVERITY 
(PGIS) AND PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) .......105 
APPENDIX 7: 
HUNGER ASSESSMENT SCALE ................................................107 


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APPENDIX 8: 
NEW YORK HEART ASSOCIATION (NYHA) 
CLASSIFICATION ................................................................................................108 
 


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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: 
  
 
 
 
  
Quality Assurance 
Helsinn Healthcare SA: 
 


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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-17-20 
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 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 while 


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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, 
OR 


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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 
prior to screening. Patient should not have plans to 


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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 
interval durations, such as any of the antiarrhythmic 


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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 
because, in order to declare the test component (anamorelin) 


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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 
in weight (≥ to a predefined threshold) (H0dtw), the secondary 


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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.  
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-17-20 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 effective 


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therapy to address weight loss and anorexia symptoms. Therefore ANAM-17-20 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 
correcting for the programming error were performed and these results confirmed high 


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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. 
 
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 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. 


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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 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 


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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 
• 
This includes patients initiating/planning to initiate chemotherapy and/or 
radiation therapy within ±14 days of randomization. 


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• 
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 be asked to 


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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 
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 


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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 
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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 
− Is a congenital anomaly or birth defect 


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− 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 use 


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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-17-20 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%).  
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 


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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 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 


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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 
Section 9.4.1), the imputation of the values will be done at the level of the visit for the raw 


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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 
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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 ≥ 5% body weight 


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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. 
No formal test will be used for “between groups” comparison. All AEs will be listed. 


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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 (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 


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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 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 


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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 
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 


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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 
the source documents. Source data verification will be regularly performed by the blinded 
study monitor.  


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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 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 


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[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 and/or the Investigator shall 
delay the publication or presentation of the Independent Submission for up to sixty (60) 


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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 

SAP_001.pdf: 
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 STATISTICAL ANALYSIS PLAN 
 
 
 
 
Sponsor 
 
Helsinn Healthcare SA 
Via Pian Scairolo 9 
6912 Lugano, Switzerland 
Phone: +41 91 985 21 21 
Fax: +41 91 985 21 22 
 
Clinical Trial Protocol 
Identification No. 
 
ANAM-17-20 
 
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). 
 
 
 
Trial Phase 
Phase 3 
 
Investigational Medicinal 
Product(s) 
 
Anamorelin HCl 
Clinical Trial Protocol 
Version 
 
Final (v5.A/5.0) – 13-Jul-2022 
Statistical Analysis Plan 
Author 
 
, Biostatistician,  
, Biostatistician 
Business & Decision Life Sciences 
 
, Senior Biostatistician 
Consultant 
Helsinn Healthcare SA 
Statistical Analysis Plan 
Date and Version 
 
12 May 2023 
Final v1.0 
 
 


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SIGNATURES PAGE 
 
Statistical Analysis Plan - Protocol number: ANAM-17-20 
Title of the protocol:  
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). 
 
 
Sponsor’s biostatistician 
Name: 
 
Function: Senior Biostatistician Consultant 
 
Signature & Date: 
 
 
 
 
Helsinn Healthcare SA 
Via Pian Scairolo 9 
6912 Lugano, Switzerland 
 
 
 
 
 
 
Sponsor’s Clinical Operation Manager 
Name: 
 
Function: Manager, Clinical Operations 
 
Signature & Date:
 
Helsinn Healthcare SA 
Via Pian Scairolo 9 
6912 Lugano, Switzerland 
 
 
 
 
 
 
 
 
B&D author of the SAP 
Name: 
 
Function: CRO Biostatistician 
Business & Decision Life Sciences 
Rue Saint Lambert 141 
1200 Brussels, Belgium 
 
Signature & Date:
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................. 3 
1. 
LIST OF ABBREVIATIONS ................................................................................ 7 
2. 
MODIFICATION HISTORY ................................................................................. 9 
3. 
PURPOSE OF THE STATISTICAL ANALYSIS PLAN ..................................... 10 
4. 
STUDY DESIGN ............................................................................................... 11 
4.1. 
Study Design ........................................................................................................................... 11 
4.2. 
Treatments .............................................................................................................................. 14 
4.3. 
Questionnaires ....................................................................................................................... 14 
4.3.1. 
Functional Assessment of Anorexia/Cachexia Therapy (FAACT) ................................... 14 
4.3.2. 
Functional Assessment of Chonic Illness Therapy – Fatigue (FACIT-F) ........................ 14 
5. 
OBJECTIVES .................................................................................................... 15 
5.1. 
Estimands ............................................................................................................................... 15 
6. 
STUDY ENDPOINTS ........................................................................................ 16 
6.1. 
Efficacy Endpoints ................................................................................................................. 16 
6.1.1. 
Primary Efficacy Endpoints .............................................................................................. 16 
6.1.2. 
Secondary Efficacy Endpoints ......................................................................................... 16 
6.1.3. 
Exploratory Efficacy Endpoints ........................................................................................ 16 
6.2. 
Safety Endpoints .................................................................................................................... 17 
7. 
STUDY METHODS AND STATISTICAL PRINCIPLES .................................... 18 
7.1. 
Randomization ........................................................................................................................ 18 
7.2. 
Sample Size ............................................................................................................................. 18 
7.3. 
Statistical Testing ................................................................................................................... 19 
7.3.1. 
Testing the co-primary endpoints .................................................................................... 20 
7.3.2. 
Testing the secondary endpoints ..................................................................................... 20 
8. 
GENERAL CONSIDERATION FOR STATISTICAL ANALYSIS ...................... 22 
8.1. 
Descriptive Statistics ............................................................................................................. 22 


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8.2. 
Addressing intercurrent events ............................................................................................ 22 
8.2.1. 
Intercurrent event death ................................................................................................... 22 
8.2.2. 
Intercurrent event study drug discontinuation .................................................................. 22 
8.3. 
Handling of missing data ....................................................................................................... 23 
8.3.1. 
Efficacy Missing Data ...................................................................................................... 23 
8.3.2. 
Missing Date on concomitant medications ...................................................................... 23 
8.3.3. 
Questionnaires Missing Data ........................................................................................... 24 
8.3.4. 
Overlapping/Duplicated Diaries ....................................................................................... 24 
8.3.5. 
Missing Date on Adverse Events ..................................................................................... 25 
8.4. 
Covariates ............................................................................................................................... 25 
8.5. 
Interim Analysis ...................................................................................................................... 25 
8.6. 
Subgroups analyses .............................................................................................................. 25 
8.7. 
Visit windows .......................................................................................................................... 26 
8.8. 
Definitions ............................................................................................................................... 26 
8.9. 
Other Considerations: Handling impact of COVID-19 pandemic ...................................... 28 
8.9.1. 
Handling Impact of COVID-19 in the Statistical Analysis ................................................ 28 
9. 
STUDY POPULATION ...................................................................................... 29 
9.1. 
Trial Subjects .......................................................................................................................... 29 
9.1.1. 
Analysis Sets ................................................................................................................... 29 
9.1.2. 
Protocol Deviations .......................................................................................................... 29 
9.1.3. 
Disposition of Subjects and Discontinuations .................................................................. 29 
9.2. 
Demographics and Other Baseline Characteristics ........................................................... 30 
9.2.1. 
Demographics .................................................................................................................. 30 
9.2.2. 
ECOG Status at screening .............................................................................................. 30 
9.2.3. 
Stratification factors at V2 (randomization) ...................................................................... 30 
9.2.4. 
Body Weight and 5-IASS at V1 (Screening) and V2 (Randomization) ............................ 30 
9.2.5. 
Vital Signs at screening ................................................................................................... 31 
9.2.6. 
Reproductive Status ........................................................................................................ 31 
9.2.7. 
Prior Body Weight Loss at screening .............................................................................. 31 
9.2.8. 
Medical History and Concomitant Diseases .................................................................... 31 
9.2.9. 
NSCLC status at Diagnosis and study Entry ................................................................... 32 
9.2.10. 
Physical examination ....................................................................................................... 32 
9.3. 
Prior and Concomitant Medications/Procedures ................................................................ 32 
9.3.1. 
Prior/Concomitant Medications (excluding NSCLC treatment) ....................................... 33 
9.3.2. 
Prior/concomitant Procedures (excluding NSCLC treatment) ......................................... 33 
9.3.3. 
Prior/Concomitant Cancer treatment ............................................................................... 33 
9.3.4. 
Prior/concomitant Radiotherapy/Surgery ......................................................................... 33 
9.4. 
Treatment Compliance ........................................................................................................... 33 
10. EFFICACY ANALYSIS ..................................................................................... 35 


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10.1. 
Primary Efficacy Endpoints ................................................................................................... 35 
10.1.1. 
Primary efficacy endpoint derivation ................................................................................ 35 
10.1.2. 
Primary efficacy analyses ................................................................................................ 35 
10.1.3. 
Sensitivity analyses ......................................................................................................... 36 
 Control-based imputation ............................................................................................ 36 
 Fluid retention replacement analysis ........................................................................... 36 
 COVID-19 sensitivity analysis ..................................................................................... 37 
 Mis-stratification sensitivity analysis ............................................................................ 37 
10.1.4. 
Supportive analyses ........................................................................................................ 38 
 Analyses on the FAS. .................................................................................................. 38 
 Analysis on the PP set ................................................................................................ 38 
 Analysis on subgroups of the co-primary endpoint ..................................................... 38 
 Premature discontinuation and retrieved dropouts ..................................................... 38 
10.2. 
Secondary Efficacy Endpoints .............................................................................................. 38 
10.2.1. 
Secondary efficacy endpoints derivation ......................................................................... 39 
10.2.2. 
Secondary efficacy endpoints analyses .......................................................................... 42 
10.2.3. 
Secondary efficacy analysis on subgroups ..................................................................... 42 
10.3. 
Exploratory Endpoints ........................................................................................................... 42 
10.3.1. 
Exploratory endpoints derivation. .................................................................................... 42 
 Mean Change from baseline over X Weeks ................................................................ 42 
 Percentage of Change in Body Weight ....................................................................... 42 
 Composite Clinical Response (CCR) .......................................................................... 43 
 Achievement of responder threshold........................................................................... 43 
 Change from baseline ................................................................................................. 43 
10.3.2. 
Exploratory endpoints analyses. ...................................................................................... 43 
 Mean Change from baseline over X Weeks ................................................................ 43 
 Change from baseline ................................................................................................. 44 
 Responder Analysis (CCR and Achievement of responder threshold) ....................... 44 
 Correlations and scatter plots ...................................................................................... 44 
 PGIS, PGIC and Hunger assessment ......................................................................... 44 
 Change from baseline to Week 12 in body weight (categorical) ................................. 45 
11. SAFETY ANALYSIS ......................................................................................... 46 
11.1. 
Exposure ................................................................................................................................. 46 
11.2. 
Adverse Events ....................................................................................................................... 47 
11.2.1. 
Classification of Adverse Events ..................................................................................... 47 
11.2.2. 
Adverse Events of Special Interest (AESI) ...................................................................... 48 
11.2.3. 
Summaries of Adverse Events ........................................................................................ 48 
11.2.4. 
Summaries of Adverse Events by Maximum CTC grade Severity .................................. 49 
11.2.5. 
Summaries of Adverse Events by Maximum relationship to the study treatment ........... 49 
11.2.6. 
Summaries of TEAEs of Special Interest ........................................................................ 49 
11.3. 
Laboratory Data ...................................................................................................................... 49 
11.4. 
Vital Signs ............................................................................................................................... 50 
11.5. 
Electrocardiogram (ECG)....................................................................................................... 51 
11.6. 
Physical Examination ............................................................................................................. 51 


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11.7. 
ECOG Performance Status .................................................................................................... 51 
11.8. 
Overall Survival ...................................................................................................................... 52 
11.9. 
Tumor Assessments .............................................................................................................. 52 
12. APPENDICES ................................................................................................... 53 
12.1. 
Missing value imputation process ........................................................................................ 53 
12.1.1. 
Imputation rules ............................................................................................................... 53 
 Imputation for Intermittent missing values (non-monotonic missingness) .................. 53 
 Imputation rules for Non-intermittent missing values (monotonic missingness) ......... 54 
12.2. 
Statistical Software ................................................................................................................ 57 
12.2.1. 
Single/Multiple imputation ................................................................................................ 57 
 Placebo (control-based) imputation ............................................................................. 57 
 MAR imputation ........................................................................................................... 58 
 Worst value imputation ................................................................................................ 58 
 Combining the imputations .......................................................................................... 58 
12.2.2. 
Data Analysis ................................................................................................................... 59 
12.2.3. 
Pooling of the analysis ..................................................................................................... 59 
12.3. 
Questionnaires scoring guidelines ...................................................................................... 60 
12.4. 
Validation and QC Plan .......................................................................................................... 63 
12.5. 
Mock Tables ............................................................................................................................ 63 
13. CHANGES IN THE PLANNED ANALYSIS FROM STUDY PROTOCOL ......... 64 
14. REFERENCES .................................................................................................. 66 
 
 
 


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1. LIST OF ABBREVIATIONS 
 
5-IASS 
5-item Anorexia Symptom Subscale score 
ACS 
Anorexia/Cachexia Subscale 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of specific interest 
ALT  
Alanine Aminotransferase 
ANAM 
Anamorelin 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AST 
Aspartate Aminotransferase 
BDRM 
Blinded Data Review Meeting 
BL 
Baseline 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CDISC 
Clinical Data Interchange Standards Consortium 
CCR 
Composite clinical response 
CI 
Confidence Interval 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group  
ePRO 
Electronic Patient Reported Outcome 
EOS 
End of Study 
EOT 
End of Treatment 
FAACT 
Functional Assessment of Anorexia/Cachexia Treatment 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FACIT-F 
Functional Assessment of Chronic Illness Therapy-Fatigue 
FACIT-G 
Functional Assessment of Cancer Therapy - General 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FU 
Follow up 
GCP 
Good Clinical Practices 
GGT 
Gamma glutamyl transferase 
HAS 
Hunger Assessment scale  
HbA1c 
Hemoglobin A1c 
HLGT 
High Level Group of Terms 
HLT 
High Level Term 
HR 
Hazard Ratio 
IC 
Informed Consent 
ICH 
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ISS 
Integrated Summary of Safety 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
Kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LLT 
Lowest Level Term 
LS 
Least Squares 
MAR 
Missing at Random 
max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Authorities 
MI 
Multiple Imputation 
mg 
Milligram 
min 
Minimum 
MNAR 
Missing not at Random 
NSCLC 
Non-Small Cell Lung Cancer 
OR 
Odds Ratio 
PD 
Protocol Deviation 
PE 
Physical Examination 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PP 
Per protocol 
PT 
Preferred Term 
Q1 
25th percentile or lower quartile 
Q3 
75th percentile or higher quartile 
QD 
Once daily 
QC 
Quality Control 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SI 
Standard International 
SMQ 
Standardized MedDRA Queries 
SOC 
System Organ Class (in MedDRA) 
TEAE 
Treatment-Emergent Adverse Event 
TEAESI 
Treatment-Emergent Adverse Event of Special Interest 
TLFs 
Tables, Listings and Figures 
TOI 
Trial Outcome Index 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 
 
 


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2. MODIFICATION HISTORY 
 
Unique Identifier 
for SAP Version 
Date of SAP 
Version 
Author 
Changes from the 
Previous Version 
Draft v0.1 
10-Dec-2018 
 
 
Draft v0.2 
29-Dec-2018 
 
Internal review 
Draft v0.3 
09-Jan-2019 
 
Incorporation of 
Mock tables 
Draft v0.4 
25-Mar-2020 
 
Update to 
version3.0 of study 
protocol 
Draft v0.5 
25-Jan-2021 
 
Update of parts 
related to safety 
and demography 
Draft v0.6 
02-Jun-2021 
 
Update to version 
4.0 of study 
protocol 
Draft v0.7 
17-Dec-2021 
 
Update to version 
5.A of study 
protocol  
Draft v0.8 
20-Jul-2022 
 
Update to version 
5.A/5.0 of study 
protocol  
Draft v0.9 
30-Nov-2022 
 
Update to 
algorithms for 
missing 
imputation.  
Added new 
analysis for 
COVID-19 and 
exploratory 
analyses. 
Restyling of the 
SAP. 
Final v1.0 
12-May-2023 
 
 
Implementation of 
post-BDRM 
updates, final 
rewording and 
formatting. 
Finalization of the 
document. 
 
 
 


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3. PURPOSE OF THE STATISTICAL ANALYSIS PLAN 
 
This Statistical Analysis Plan (SAP) is intended to document technical and detailed 
specifications for the analysis of the data collected in order to generate the tables and 
listings to support the analysis of this phase 3 Randomized Clinical Trial, evaluating 
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). 
The structure and content of this SAP are intended to provide sufficient detail to meet 
the requirements identified by Regulatory Agencies and International Conference on 
Harmonization of Technical Requirements for Registration of Pharmaceuticals for 
Human Use (ICH): Guidance on Statistical Principles in Clinical Trials.  
The SAP is also prepared in accordance with the study protocol V5.A / V5.0 and will 
concentrate on the detailed description of the planned analyses to be carried out to 
support the completion of the Clinical Study Report (CSR) for the study. 
All statistical analyses will be carried out after the database is locked and treatment 
allocation is unblinded. 
 
 
 


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4. STUDY DESIGN  
 
4.1. 
Study Design 
Weight loss and anorexia (including appetite loss) represent common and debilitating 
manifestations in patients with advanced NSCLC. Despite the high prevalence and the 
association with diminished life-expectancy, the therapeutic advance in managing 
these symptoms has been so far limited and the treatment of malignancy associated 
weight loss and anorexia in cancer patients remains an area of highly unmet medical 
need. 
The study is a multicenter, randomized, double-blind, parallel-group, placebo-
controlled study to evaluate the efficacy and safety of anamorelin HCl. A total of 318 
patients with advanced NSCLC with cachexia have been randomized 1:1 to 
anamorelin HCl 100 mg or placebo, taken orally once daily (QD) for a total of 24 weeks. 
Patients were instructed to take the study drug at least 1 hour before their first meal of 
the day. For each patient the study lasted up to approximately 27 Weeks, 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 is defined as having completed the Study if the follow-up visit (Visit 11) was 
completed. 
The study being placebo-controlled, all comparisons for the efficacy parameters will be 
done in order to demonstrate superiority of anamorelin over placebo. 
 


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Study Design and Schedule of Assessments  
Assessment 
Screening 
Visit Day 
Treatment Period 
Follow-up 
Period 2  
Day 
-7 to -1 
1 
22 
(+3) 
43 
(+3) 
64 
(+3) 
85 
(+3) 
106 
(+3) 
127 
(+3) 
148(
+3) 
169 
(+3) 
183 (+3) 
Week 
-1 
1 
3 
6 
9 
12 
15 
18 
21 
24 
26 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG PS 
X 
 
 
 
X 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height and BMI 
X 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry/Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HbA1c 
X 
 
 
 
 
X 
 
 
 
X 
 
Urine pregnancy 
X 
X 
 
 
X 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
X 
 
 
 
 
X 
 
Administer FAACT questionnaire 12-item A/CS domain only 
X 
 
 
 
 
 
 
 
 
 
 
Administer FACIT questionnaires1 and Hunger Assessment Scale 
questionnaires 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Administer PGIS questionnaires for body weight and anorexia 
X 
 
 
X 
X 
 
 
 
 
 
 
Administer PGIC questionnaires for body weight, anorexia and overall 
condition, 
 
 
 
X 
X 
 
 
 
 
 
 
CT scan 
X 
→ 
→ 
→ 
→ 
X 
→ 
→ 
→ 
→ 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior and concomitant medications (including NSCLC treatment) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Dispense new and/or return blister card for study drug dosing; check 
compliance  
 
X 
X 
X 
X 
X 
X 
X 
X 
End 
 
1) 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 


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2) Follow-up period: by telephone 


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4.2. 
Treatments 
Group 1 / Test group – 100 mg anamorelin HCl (once per day) 
Group 2 / Control group – placebo (once per day) 
 
4.3. 
Questionnaires 
The derivations of all the scores and algorithms described in the present section will 
be obtained directly by the eCOA/ePRO vendor (Clario, formerly eResearch 
Technology). No further calculation or derivation will be done at SDTM or ADaM level. 
The derived variables will be reported in SDTM.QS and ADaM.ADQOL domains after 
confirmatory crosschecks performed by the CRO and Helsinn.  
Algorithm will be reported in SDTM Define. 
4.3.1. 
Functional Assessment of Anorexia/Cachexia Therapy 
(FAACT) 
The FAACT measure is a 39-item questionnaire which combines the 27 items of the 
FACT-G (Functional Assessment of Cancer Therapy-General) questionnaire to the 12-
item measure of the FAACT A/CS which examines patients’ perception of Anorexia 
Cachexia symptoms and concerns.  
Each item is scored by the patient on a 5-point Likert-type scale, ranging from 0 (Not 
at All) to 4 (Very Much). 
Details on scoring are reported in Appendix 12.3. 
4.3.2. 
Functional Assessment of Chonic Illness Therapy – 
Fatigue (FACIT-F) 
The FACIT-Fatigue subscale is a 13-item measure which is summed to the 27-item 
FACT-G score to calculate the FACIT-F Total score of the 40-item FACIT-F measure; 
each item of the FACIT-Fatigue scale is to be scored by the patient on a 5-point Likert-
type scale, ranging from 0 (Not at All) to 4 (Very Much). 
Details on scoring are reported in Appendix 12.3. 
 
 
 


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5. OBJECTIVES 
The primary objective of the present ANAM-17-20 study is to demonstrate superiority 
of anamorelin vs. placebo on the gain in body weight and improvement of anorexia 
symptoms in patients with advanced non-small cell lung cancer (NSCLC) with BMI<20 
kg/m2 and involuntary weight loss of more than 2% in the 6 months preceding 
screening. The secondary objective is to evaluate the safety and tolerability of 
anamorelin HCl, and to further evaluate anamorelin efficacy profile. 
5.1. 
Estimands 
The analysis to address this objective has been developed in consideration of 
ICHE9(R1). Specifically, two intercurrent events have been identified: study drug 
discontinuation and death.   
As to the study drug discontinuation, the “treatment policy” strategy will be applied to 
all efficacy endpoints (primary/secondary/exploratory) declared in Section 6 (apart 
from HAS and PGIS/PGIC). Efforts have been made to retain all patients in study 
follow-up, whether or not they have discontinued the study treatment. In view of the 
statistical analysis, methods for missing imputation will be applied in case of 
assessments not performed after study discontinuation (Appendix 12.1).  
In the target population of patients with advanced NSCLC it is expected that death will 
be mostly due to the progression of the underlying malignant 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. Therefore, 
a “while-on-treatment” type strategy for death (i.e. while alive) is applied. 
 
 


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6. STUDY ENDPOINTS 
 
6.1. 
Efficacy Endpoints 
6.1.1. 
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 (5-IASS) from baseline over 
12 weeks. 
6.1.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• Duration of treatment benefit in weight gain (≥ 0 kg) over 12 weeks. 
• Duration of treatment benefit in weight gain (≥ 1.5 kg) over 12 weeks. 
• Duration of treatment benefit in anorexia symptoms (≥0 points) over 12 weeks, as 
measured by the 5-item Anorexia Symptom Subscale. 
• Duration of treatment benefit in 5-item Anorexia Symptom Subscale (increase ≥ 3 
points) over 12 weeks. 
• Mean change in FAACT 12-item A/CS domain from baseline over 12 weeks. 
• Mean change in FACIT-F 13-item subscore from baseline over 12 weeks 
• Mean change in FAACT total score from baseline over 12 weeks.  
6.1.3. 
Exploratory Efficacy Endpoints 
• Mean change in body weight from baseline over 6, 9, 15, 18, 21, and 24 weeks. 
• Mean change in patient-reported anorexia symptoms from baseline over 6, 9, 15, 
18, 21, and 24 weeks, as measured by the 5-item Anorexia Symptom Subscale. 
• Mean change in FAACT total score from baseline over 6, 9, 15, 18, 21, and 24 
weeks. 
• 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. 
• Clinically meaningful gain in body weight (1.5 kg) from baseline to Week 3, 6, 9, 
12, 15, 18, 21, and 24. 
• Clinically meaningful increase in 5-item Anorexia Symptom Subscale (3 points) 
from baseline to Week 3, 6, 9, 12, 15, 18, 21, and 24. 


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• 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 
total score, FACT-G total score, FAACT TOI, the 12-item A/CS domain and the 
4-item Anorexia Concerns Subscale. 
• Changes from baseline to Week 3, 6, 9, 12, 15, 18, 21, and 24 in 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. 
• Changes from baseline to Week 3, 6, 9, 12, 15, 18, 21, and 24 in the following 
items extracted from Physical Well-Being and Functional Well-Being domains: 
o GP1, GP7, GF5, GF6, GF7. 
• Changes from baseline to Week 3, 6, 9, 12, 15, 18, 21, and 24 in the following 
items extracted from the 12-item A/CS domain: 
o ACT1, ACT2, ACT4, ACT13. 
• Changes from baseline to Week 3, 6, 9, 12, 15, 18, 21, and 24 in the following 
items extracted from the FACIT-F (Fatigue) questionnaire: 
o HI7, HI12, AN2, AN5, AN12. 
• Correlation between Weight gain and improvement on the patient reported 
anorexia score from baseline to Week 3, 6, 9, 12, 15, 18, 21, and 24. 
• Correlation between Weight gain and improvement on the patient reported 
anorexia score from baseline over 12 weeks. 
 
6.2. 
Safety Endpoints 
• Treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) 
• Changes from Baseline in vital signs, ECG parameters and laboratory 
assessments (chemistry, hematology, and urinalysis) 
• Shifts from Baseline in laboratory assessments, physical examination and ECG 
overall interpretation. 
• Overall Survival 
• Overall Response based on tumor assessment 
 


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7. STUDY METHODS AND STATISTICAL PRINCIPLES 
 
7.1. 
Randomization 
Central randomization (IWRS) was stratified by: 
• Line of systemic anti-cancer treatment (i. first vs ii. second vs iii. third line or 
higher),  
• Type of anti-cancer therapy (immunotherapy vs non-immunotherapy), 
• Baseline score of 5-item Anorexia Symptom Subscale (≤10 vs >10). 
 
7.2. 
Sample Size 
At the time when the trial was initiated, the primary endpoint was the Composite Clinical 
Response (CCR) rate. The sample size was determined based on results obtained in 
patients participating to the previous trials (HT-ANAM-301 and HT-ANAM-302 (4), (5)). 
The retrospectively observed CCR rates, in the subset of patient with baseline BMI 
<20 kg/m² and ongoing problems with appetite/eating as defined by inclusion criterion 
5, were 20% for anamorelin and 7.5% for placebo at week 12, and 21.0% vs. 6.0% at 
week 9. 
To be conservative the study was adequately powered to detect an improvement in 
CCR Rate at week 9 from 7.5% in the placebo group to 20.0% for the anamorelin 
group. This improvement would be detected with 90% power, using a logistic 
regression for the CCR, with a sample size of 316 patients (158 patients per arm) and 
a 2-sided 0.05 significance level.   
In the latest version (V5.0-V5.A) of the study protocol, co-primary endpoints were 
defined as follows: 
- 
mean change in body weight over 12 weeks 
- 
mean change in 5-IASS over 12 weeks. 
With the fixed sample size of 158 patients per arm, study power was computed by 
means of simulations based on patients participating to previous company trials 
comparing anamorelin and placebo. Data from these trials were resampled in an 
unbalanced and in a balanced way with respect to 5-IASS at baseline (<= or >10), as 
those studies were not stratified and were unbalanced between treatment groups in 
terms of 5-IASS. To explore the power of the test procedure for the new endpoint, 
many scenarios to set assumptions for missing data were simulated, based on choices 
between different options for the following topics: 
- 
The patient’s baseline characteristics of the sample to be obtained (with 
BMI≤20, ACS-12≤37, 5-IASS≤17, fulfilling inclusion criteria 4 and 5, with/without 
missing data at baseline, with/without 5-IASS missing at week 3) 
- 
The kind of imputation method adopted (fully MAR or MNAR+MAR based on 
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- 
The variables to be included as covariates in the imputations (from a large 
number to no covariates) 
- 
The process for the MNAR+MAR imputation method: the different sets of 
subjects contributing to the imputations (all subjects with data vs. all complete 
subjects) and different sequential steps for applying MAR and MNAR 
- 
The method of analysis (ANOVA with the 5-IASS stratum included in the 
ANOVA model, then including/excluding in the model the baseline covariate of 
the variable under analysis) 
For each scenario the number of simulated studies ranged from 400 to 1000. 
The simulations showed a power close to 100% to test an effect size in terms of mean 
change in body weight over 12 weeks approximately equal to 1.8 kg. The power to test 
an effect size in terms of mean change in 5-IASS over 12 weeks within the range of 
1.2 – 1.4 was showed to range between 78% and 87%. This leads to a joint power for 
the two co-primary endpoints of at least 78%. 
 
7.3. 
Statistical Testing 
The primary and the secondary efficacy endpoints will be evaluated using a hierarchy 
for testing in order to control type I error rate. The order of testing will be as follows: 
• The mean change in body weight over 12 weeks (H0W) and the mean change 
in 5-item Anorexia Symptom Subscale over 12 weeks (H0A), assessed as co-
primary endpoints; Definition and derivation of the co-primary efficacy 
endpoints is given in Section 10.1.1. 
• The secondary efficacy endpoint related to the duration of treatment benefit 
over 12 weeks in body weight gain (≥ 0 kg) (H0d0W). 
• The secondary efficacy endpoint related to the duration of treatment benefit 
over 12 weeks in body weight gain (≥ 1.5 kg) (H0dtW). 
• The secondary efficacy endpoint related to the duration of treatment benefit 
over 12 weeks in 5-item Anorexia Symptom Subscale (≥0 points) (H0d0A). 
• The secondary efficacy endpoint related to the duration of treatment benefit 
over 12 weeks in 5-item Anorexia Symptom Subscale (≥ 3 points) (H0dtA). 
• The secondary efficacy endpoint related to the mean change in FAACT 12-item 
A/CS domain score from baseline over 12 weeks (H0mF).  
• The secondary efficacy endpoint related to the mean change in FACIT-F 
(H0mFF) from baseline over 12 weeks. 
• The secondary efficacy endpoint related to the mean change in FAACT total 
score (H0mFt) from baseline over 12 weeks. 
Definition and derivation of the secondary efficacy endpoints is given in Section 10.2.1. 
Each of these tests will be done sequentially at the level of 0.05 bilateral.  


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7.3.1. 
Testing the co-primary endpoints 
To preserve the experimental Type I error rate (threshold of 0.05 two-sided), 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 null hypothesis for the first co-primary endpoint of mean change in body 
weight from baseline over 12 weeks (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 from baseline over 12 weeks for the 
anamorelin arm and MWp is the mean change in body weight from baseline over 12 
weeks for the placebo arm. 
- 
The null hypothesis for the other co-primary endpoint of mean change from 
baseline over 12 weeks 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 from baseline over 12 weeks in 5-item Anorexia 
Symptom Subscale for the anamorelin arm and MAp is the mean change from baseline 
over 12 weeks in 5-item Anorexia Symptom Subscale for the placebo arm.   
7.3.2. 
Testing the secondary endpoints 
- 
The null hypothesis concerning the first secondary endpoint of duration of 
treatment benefit over 12 weeks in body weight (≥0 kg) ((H0d0w) and the 
corresponding alternative hypothesis (H1d0w) are defined as: 
H0d0w: D0Wa = D0Wp 
H1d0w: D0Wa ≠ D0Wp 
Where D0Wa is the duration of treatment benefit over 12 weeks in body weight gain (≥ 
0 kg) for the anamorelin arm and D0Wp is the duration of treatment benefit over 12 
weeks in body weight gain 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. 
- 
The null hypothesis concerning the secondary endpoint of duration of treatment 
benefit in body weight over 12 weeks (≥ 1.5 kg) (H0dtW) and the corresponding 
alternative (H1dtW) are defined as: 
H0dtW: DtWa = DtWp 
H1dtW: DtWa ≠ DtWp 


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Where DtWa is the duration of treatment benefit over 12 weeks in weight (≥ 1.5 kg) for 
the anamorelin arm and DtWp is the duration of treatment benefit over 12 weeks in 
weight for the placebo arm. 
H0dtW will be tested using a Type-I 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 over 12 weeks in 5-item Anorexia 
Symptom Subscale (≥ 0 points) for the anamorelin arm and D0Ap is the duration of 
benefit over 12 weeks in 5-item Anorexia Symptom Subscale for the placebo arm. 
H0dtA: DtAa = DtAp 
H1dtA: DtAa ≠ DtAp 
Where DtAa is the duration of treatment benefit over 12 weeks in 5-item Anorexia 
Symptom Subscale (≥ 3 points) for the anamorelin arm and DtAp is the duration of 
benefit over 12 weeks in 5-item Anorexia Symptom Subscale for the placebo arm. 
H0mf: MFa = MFp 
H1mf: MFa ≠ MFp 
Where MFa is the mean change from baseline over 12 weeks in FAACT 12-item A/CS 
domain score in the anamorelin arm and MFp is the mean change from baseline over 
12 weeks in FAACT 12-item A/CS domain score in the placebo arm.  
Similar hypothesis systems are set-up for FACIT-F (H0mFF, H1mFF) and FAACT total 
score (H0mFt, H1mFt). 
 
 
 


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8. GENERAL CONSIDERATION FOR STATISTICAL ANALYSIS 
 
8.1. 
Descriptive Statistics 
All analyses will be conducted using SAS version 9.4 or higher. 
The following conventions will be used when presenting summary statistics: 
• 
Continuous variables will be summarized using the following descriptive 
statistics: number of subjects (n), mean, standard deviation (SD) median, 
minimum (min), maximum (max), 25th percentile (lower quartile or Q1) and 75th 
percentile (upper quartile or Q3).  
• 
Categorical and binary variables will be summarized by the number of subjects 
(n) and the percent of subjects in each category. For AE tables, the number of 
events (E) will also be presented. Percentages will be presented to 1 decimal 
place.  
• 
The number of subjects or observations will be presented as an integer. 
• 
Mean, lower quartile and upper quartile will be presented to 1 decimal place more 
than the raw value. 
• 
Min, max and median will be presented to the same number of decimal places as 
the raw value. 
• 
Standard deviation will be presented to 1 decimal place more than the mean 
value, up to a reasonable number of decimal places (i.e., rarely more than 3 
decimal places unless the nature of the data suggests this). 
• 
The denominator for percentage calculations will be the number of non-missing 
observations at that visit. Where this isn’t appropriate, the number of subjects in 
the relevant analysis set will be used. 
 
8.2. 
Addressing intercurrent events 
8.2.1. 
Intercurrent event death 
The data from the previous trials HT-ANAM-301 (4) and HT-ANAM-302 (5) suggest a 
positive effect of anamorelin on the weight and the 5-IASS. Death from underlying 
disease is rather inevitable in this target population and it is anticipated to not reflect a 
failure of study treatment. In accordance with the ICHE9 R1 guideline, the 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, for patients dying before the completion of the period, no imputation 
strategy will be adopted for outcomes after death and only values collected before 
death will be used for the evaluation of the endpoint.  
8.2.2. 
Intercurrent event study drug discontinuation 
The treatment policy strategy will apply to address study drug discontinuation. 


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Due to the nature of the patients’ underlying disease, a non-ignorable amount of 
missing data is expected in this trial. Every effort has been made to collect data from 
the protocol-specified assessments; patients were asked to continue to participate in 
the study and complete planned visits up to the end of the study period (Week 24) even 
if they have permanently discontinued treatment with the IMP (“retrieved dropout” 
approach). 
Reason for treatment discontinuation will be collected in the CRF and will be 
considered for use in investigating possible unexpected patterns of missing data. To 
minimize the risk of bias in the analysis, specific rules for single/multiple imputation will 
be adopted 
 
8.3. 
Handling of missing data  
8.3.1. 
Efficacy Missing Data  
The preferred statistical approach to manage the missing values due to the intercurrent 
event was the Multiple Imputation (MI) using retrieve dropouts (e.g.: assessments in 
patients no more under randomized treatment). However, at the BDRM it was 
confirmed that only a small number of retrieved dropouts was available, making 
unfeasible the established approach. For this reason, a control-based MI approach will 
be adopted by considering a Missing Not at Random (MNAR) mechanism for missing 
data: imputation of values in the active arm will be done using the non-missing values 
from the control group. This approach does not assume benefits for anamorelin in case 
of intercurrent event and limits a post-discontinuation clinical effect to that of placebo.  
Efficacy missing data will be imputed on the bases of rules described in Appendix 12.1. 
For missing data the imputation of the values will be done at the level of the visit for 
the raw values (for instance weight). 
Post-discontinuation missing date of visit X will be imputed by adding 3 weeks to the 
date of the previous available visit X-1. The date of visit X+1 will be imputed by adding 
3 weeks to the date of Visit X imputed in the previous step and so on.     
Imputed values will then be used to derive primary, secondary and exploratory 
endpoints according to rules reported in Section 10.1.1, 10.2.1 and 10.3.1.  
Datasets including imputed values and resulting derived variables will be used for all 
efficacy endpoints (primary, secondary and exploratory).  
8.3.2. 
Missing Date on concomitant medications 
 
In the determination of whether a medication is taken during the Treatment Period, the 
following rules for missing and partial dates will be applied: 
• 
If the end date is before the first dose of study medication, then the medication 
is a prior medication, regardless of whether or not the start date is missing or 
partially missing 


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• 
If the end date is on or after the date of the first dose of study medication, then 
the following rules will be applied for missing or partially missing start dates: 
- 
If the start date is completely missing, then the medication will be assumed 
to be concomitant. 
- 
If only the year of the start date is recorded and the year is either before 
or the same year as the date of last dose of study medication then the 
medication will be assumed to be concomitant. 
- 
If only the year of the start date is recorded and the year is after the year 
of the date of last dose of study medication, it will be considered as a post-
study treatment medication. 
- 
If only the year and the month of the start date is recorded and the month 
specified is either before or the same month as the date of last dose of 
study medication, then the medication will be assumed to be concomitant. 
- 
If only the year and the month of the start date is recorded and the month 
specified is after the month of the date of last dose of study medication, it 
will be considered as a post-study treatment medication. 
The same rules are applicable for the concomitant procedures. 
8.3.3. 
Questionnaires Missing Data  
See Section 4.3 for the questionnaires and Appendix 12.3 for Scoring guidelines. 
In cases where individual items are skipped, subscale scores can be prorated using 
the average of the other answers in the scale. A FACIT measure is considered to be 
an acceptable indicator of patient quality of life as long as overall response rate at item 
level is greater than 80% (e.g., at least 22 of 27 FACT-G items completed). This is not 
to be confused with individual subscale item response rate, which allows a subscale 
score to be prorated for missing items if greater than 50% of items are answered e.g., 
a minimum of 4 of 7 items, 4 of 6 items, etc. The total score is then calculated as the 
sum of the un-weighted subscale scores. In addition, a total score should be calculated 
only if ALL of the component subscales have valid scores. 
PGIC and PGIS questionnaires have no score derivation. 
8.3.4. 
Overlapping/Duplicated Diaries 
In some patients questionnaires recorded at screening visit (expected to be done 
between Day -7 and Day -1) were actually filled in on Day 1, just before the 
questionnaire filled in for the Visit 2, meaning that the date of screening assessment is 
the same as the date of Visit 2. These cases were checked during BDRM and minor 
protocol deviations were recorded. 
In some patients the overlapping of assessment dates happened between Visit 3 and 
Visit 10. The same questionnaire was performed twice (with a lag of few minutes) in a 
day (usually corresponding to the Day of a given Visit X). The second questionnaire 


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was entered as performed at the Visit X, while the first one was entered as referring to 
the prior Visit (X-1). For these cases the following rule will be applied: 
              If the date of assessment [Visit (X-1)] >= date of assessment Visit (X),  
then the date and collected value of questionnaire assigned to Visit X-1 will be set to 
missing. The date of assessment Visit (X-1) will be subsequently reset to the date of 
Visit (X-1) from Study Visits domain; this will be done at ADaM level. Questionnaire 
value set to missing will be imputed according to the rules described in Appendix 12.1. 
If a mismatch between the date of score assessment (i.e.: questionnaire date 
aforementioned) and the date of corresponding individual items assessment is 
detected, the date of score will be replaced with the date of individual items. If a 
mismatch between the dates of individual items assessment is detected, the maximal 
date will be used to replace the date of score. 
8.3.5. 
Missing Date on Adverse Events 
 
In the determination of whether an Adverse Event is Treatment Emergent (TEAE), the 
following rules for missing and partial dates will be applied: 
• 
If an incomplete onset date was collected for an AE, the event will be considered 
TEAE unless there is other evidence that confirms that the event was not TEAE 
(e.g.; next bullet point) 
• 
If the AE end date is before the first dose of study medication, then the AE is 
pre-treatment, regardless of whether or not the AE start date is missing or 
partially missing. 
 
8.4. 
Covariates 
The three stratification factors at randomization are used as categorical covariates in 
each statistical model:  
▪ Systemic anti-cancer treatment line (first line vs second line vs third or higher 
line)  
▪ Cancer treatment (immunotherapy vs no immunotherapy)  
▪ The 5-item Anorexia Symptom Subscale (≤10 vs >10). 
 
8.5. 
Interim Analysis 
Not applicable. No formal interim analysis is planned for this study. 
 
8.6. 
Subgroups analyses 
Subgroup analyses (specifically the analysis of the coprimary and secondary efficacy 
endpoints) will be performed for the subgroups for which numerical feasibility was 
confirmed at the BDRM, as defined by the following variables:  


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▪ Age (≤ 65 years or > 65 years) 
▪ Gender 
▪ Systemic anti-cancer treatment line (first line vs second line vs third or higher 
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 
 
8.7. 
Visit windows 
For the endpoints based on mean change and duration of benefit, the actual day of 
assessment will be used for the computation. No other visit windowing is applicable 
and planned to be done apart from corrections related to the overlapping/duplicated 
diaries described in Section 8.3.4. 
 
8.8. 
Definitions 
Baseline 
The baseline value for all efficacy analyses is defined as the value collected at Visit 2 
(randomization); if this is not available or collected day(s) later as compared to Visit 2, 
the value collected at screening visit will be used. 
For the following assessments, baseline is the value reported at Screening (V1): 
- 
ECOG PS  
- 
HbA1c  
- 
all Urinalysis parameters  
- 
the Patients’ Global Impression of Severity (PGIS) scale  
- 
the Patients' Global Impression of Change (PGIC) scale 
The baseline value for all safety analyses is defined as the last measurement 
performed before study drug administration. 
Change from Baseline 
Any “Change from baseline” variable will be computed as: 
“variable” at Visit X – Baseline, 
with X≥3 and Baseline defined as above.  
Last assessment  
Last assessment performed (body weight / 5-IASS) regardless of treatment 
discontinuation. 
Retrieved dropout 
Patient who drops the treatment but who continues to be assessed. 
Non-monotone pattern of missingness (also called “Intermittent missing 
values”) 


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Missing values may occur in the middle of a subject record (e.g., missed intermediate 
visit). It is expected that a value before the missing assessment, and a value after the 
missing assessment are available.  
Monotone pattern of missingness (also called “non-Intermittent missing values”) 
Missing values are located in a block at the end of data records (e.g., due to study 
discontinuation).  
Study Treatment Start Date 
It is the date of the first intake of the study treatment. 
End of Treatment (EOT) Date 
It is the date declared in the End of Treatment CRF Form. This date will be used in the 
derivations unless specific adjustments are needed (e.g., for actual exposure 
derivation).  
Last follow-up contact date 
It is the date of the last contact for patients alive. It is the date of last follow-up in case 
of final phone contact (Visit 11 for patients completing the study, before Visit 11 in case 
of treatment discontinuation), or the date of last performed visit in case of patient lost 
to follow-up. 
It corresponds to the date of death in case a patient died. 
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. 
Patients who completed 24 weeks treatment 
A patient will be defined as having “completed” 24 weeks treatment when the patient 
received study drug at the day of Visit 10 (either on-site or at home) and have evidence 
of treatment for all previous weeks. 
Fluid retention 
Presence of fluid retention will be assumed when either a treatment emergent AE 
associated with fluid retention is present or edema is recorded in the CRF by 
investigator at time of the assessment of weight. Specific assessments are scheduled 
at each study visit. 
After a specific review of the LLTs during the BDRM, AEs coded with the following PTs 
were confirmed as possibly impacting the weight measurements: ‘Fluid retention’, 
‘Ascites’, ‘Pleural effusion’, ‘Oedema peripheral’, ‘Oedema’. These AEs will be taken 
into account.  
Clinically meaningful thresholds for 5-IASS change and Body Weight Change 
To support with patient informed interpretation of meaningful change or stabilization, 
the results of a quantitative analysis of a separate study (7), combined with evidence 
from the embedded qualitative interview sub-study (6), support a responder definition 
of 3.0 for the 5-IASS Score and 1.5 kg weight gain for body weight. 


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These thresholds were defined in line with FDA guidance, therefore anchor-based 
methods for score interpretation were considered the primary analysis. Distribution-
based methods were used as supportive and secondary analysis using PGIS (Patient 
Global Impression of Severity) and PGIC (Patient Global Impression of Change) as 
anchors.  
For the analysis of the duration of treatment benefit the definition of a threshold to 
establish a change from baseline as clinically meaningful is provided (Sections 10.2 
and 10.2.1) 
Last value  
For Laboratory Shift Tables analysis, the Last Value is the last value reported by the 
patient during the study period.  
 
8.9. 
Other Considerations: Handling impact of COVID-19 
pandemic 
The present document and the analysis described in it, have been updated in 
compliance with the FDA guidance contained in the Conduct of Clinical Trials of 
Medical Products during the Covid-19 Public Health Emergency (Version March 2020, 
updated on August 30th 2021).  
The Sponsor provided instructions to sites during the study in order to manage and 
mitigate the COVID-19 pandemic effects on the study, particularly allowing remote 
subject visits (refer to the Guidance and contingency plan from Sponsor to Sites (8)).  
8.9.1. 
Handling Impact of COVID-19 in the Statistical Analysis 
All deviations related to the COVID-19 pandemic and resulting from the measures 
described in the Sponsor’s contingency plan have been captured and discussed during 
the BDRM. 
Sensitivity analyses have been planned based on the following considerations. Upfront 
it can be stated that: 
• A tangible impact on measurements of body weight can be expected. Body 
weight values were reported by patient at each visit during a phone call. Patients 
were asked to use their own weight scale (analog or digital). This implies a lack 
of standardization and therefore to a certain degree of variability and lower 
accuracy. 
•  A minor impact is anticipated on eCOA endpoints. During remote visit on the 
phone, patient was asked to respond to each item of each questionnaire as per 
schedule at the given visit by delegated study personnel who entered responses 
in eCOA system accordingly, and data underwent to standard transmission 
process. 
• 
There is no reason to expect any worsening in patient safety.  
 
 


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9. STUDY POPULATION 
 
9.1. 
Trial Subjects 
 
9.1.1. 
Analysis Sets 
The following study populations (analysis sets) will be considered for analysis: 
▪ The Intent-to-Treat (ITT) Set includes All randomized patients and will be 
analyzed as per planned treatment.  
▪ The Full Analysis Set (FAS) includes all randomized patients who took at least 
one dose of trial medication and for whom any post-randomization data (in 
addition to the trial medication intake) are available. The FAS will be analyzed 
as per randomization.  
▪ The Safety Set includes all patients who receive any study drug and will be 
analyzed as per actual treatment. 
▪ The Per-Protocol (PP) set is subset of the randomized patients who do not have 
major protocol violations and will be analyzed as per actual treatment. 
9.1.2. 
Protocol Deviations 
Protocol deviations (PDs) were collected and documented by the study monitors and 
medical team throughout the study period. During the data cleaning process, PDs 
detectable programmatically in the clinical database were also identified and 
documented for final discussion and categorization during the BDRM.  
Exact definition of major and minor protocol deviations affecting primary efficacy were 
specifically discussed and approved by Helsinn at the BDRM and documented in the 
meeting minutes. 
The finalization of protocol deviations and exclusions from the Per Protocol set have 
been made prior to randomization code being revealed. 
Minor and major protocol deviations identified will be summarized by treatment group 
and for all patients in the ITT Set  
A listing of all protocol deviations will also be provided. 
9.1.3. 
Disposition of Subjects and Discontinuations 
All summaries will be presented on the ITT Set. 
The number of subjects treated in the study will be presented, together with the number 
and percentage of subjects who completed the study and the number and percentage 
of subjects who withdrew from the study prematurely; a breakdown of the 
corresponding reasons for withdrawal will be presented. The number of subjects who 
discontinued the study treatment prematurely will also be presented with a breakdown 
of the corresponding reasons for study treatment discontinuation. 
A tabulation of the number and percentage of subjects randomized at each site and 
country will be summarized for all patients in the ITT Set.  


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9.2. 
Demographics and Other Baseline Characteristics 
 
9.2.1. 
Demographics 
Subject demographics will be summarized using descriptive statistics for continuous 
variables and frequency distributions (number and percentage of subjects) for 
categorical variables. Summaries will be provided overall and by treatment group at 
Screening for all defined analysis sets. 
The following demographic data and baseline characteristics will be summarized: 
• 
Age at Screening 
• 
Gender 
• 
Race and Ethnicity 
• 
Height 
• 
Weight at Screening 
• 
BMI at Screening 
If subjects have record of more than one race, then for the summary table, these 
subjects will be included in the Other Race group. BMI will be calculated from the height 
and weight values. 
All demographic data and baseline characteristics will be listed for all patients in the 
ITT Set. In the demography listing, if a subject has more than one race recorded, then 
all races selected will be listed for that subject. 
9.2.2. 
ECOG Status at screening 
ECOG status at baseline (screening) will be summarized using frequency distributions 
(number and percentage of subjects). Summaries will be provided overall and by 
treatment group for all defined analysis sets. 
ECOG status will also be listed for all patients in the ITT Set. 
9.2.3. 
Stratification factors at V2 (randomization) 
Chemotherapy line, Anti-cancer treatment (Immunotherapy/Non-immunotherapy) and 
5-IASS score used as stratification factors at randomization will be summarized using 
frequency distributions (number and percentage of subjects) for categorical variables. 
Summaries will be provided overall and by treatment group for ITT set only. 
All stratification factors will also be listed for all patients in the ITT Set.  
9.2.4. 
Body Weight and 5-IASS at V1 (Screening) and V2 
(Randomization) 
Body Weight and 5-IASS score used as co-primary endpoint for the efficacy analysis, 
will be summarized using descriptive statistics for continuous variables. Summaries for 
screening and randomization visits will be provided in a single table overall and by 
treatment group for ITT set. 
Body Weight and 5-IASS score at V1 and V2 will also be listed for all patients in the 
ITT Set.  


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9.2.5. 
Vital Signs at screening 
Vital Signs collected at screening will be summarized using descriptive statistics for 
continuous variables. Summaries will be provided overall and by treatment group for 
all defined analysis sets. 
The following Vital Signs data will be summarized: 
• 
Systolic Blood Pressure 
• 
Diastolic Blood Pressure 
• 
Pulse Rate 
• 
Respiratory Rate 
• 
Body Temperature 
All data will be listed for all patients in the ITT Set.  
9.2.6. 
Reproductive Status 
Reproductive status information will be summarized using frequency distributions 
(number and percentage of subjects) for categorical variables. Summaries will be 
provided overall and by treatment group at Screening for ITT and Safety sets. 
The following reproductive status information will be summarized: 
• 
Patient childbearing potential 
• 
Use of reliable contraceptive measures 
• 
Reason of not being childbearing potential 
All data will be listed for all patients in the ITT Set.  
9.2.7. 
Prior Body Weight Loss at screening 
Body Weight loss within 6 months prior to screening will be summarized using 
descriptive statistics for continuous variables. Summaries will be provided overall and 
by treatment group at Screening for all defined analysis sets. 
All data will also be listed for all patients in the ITT Set.  
9.2.8. 
Medical History and Concomitant Diseases 
Medical history and concomitant diseases will be coded with MedDRA dictionary 
(version 22.0).  
Medical history refers to all conditions that started and ended before the first dose of 
study drug. 
Concomitant diseases refer to all conditions started before the first dose of study drug 
and with an end date on or after the first dose of study drug. 
Medical history and concomitant diseases will be summarized in frequency tables by 
SOC and PT (sorted by descending frequency of SOC and then PT in the anamorelin 
arm) for ITT and Safety Sets.  
A listing of Medical History and Concomitant diseases will also be provided for the ITT 
Set. 


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9.2.9. 
NSCLC status at Diagnosis and study Entry 
NSCLC status at Diagnosis will be summarized using descriptive statistics for 
continuous variables and frequency distributions (number and percentage of subjects) 
for categorical variables. Summaries will be provided overall and by treatment group 
at Screening for ITT and Safety sets. 
The following information will be summarized: 
• 
Time to initial diagnosis at study screening (Year) 
• 
Stage at Diagnosis (TNM classification) 
• 
Overall stage 
• 
Site of Metastasis 
• 
Mutational Status and type of mutation 
• 
TUMOR PD-L1 Expression 
The same descriptive statistics will be provided for NSCLC status at Study Entry 
(excluding Time to initial diagnosis at study screening). 
All NSCLC status data at diagnosis and study entry will be listed for the ITT Set. 
9.2.10. 
Physical examination 
Physical examination data will be summarized using frequency distributions (number 
and percentage of subjects). Each Body System examined (General Appearance, 
Head, Eyes, Ears, Nose and Throat, Skin, Neck and so on) will be provided overall and 
by treatment group at Screening for ITT and Safety sets. 
All physical examinations will also be listed for all patients in the ITT Set.  
 
9.3. 
Prior and Concomitant Medications/Procedures 
Medication usage will be coded using the World Health Organization (WHO) Drug 
Dictionary (version WHO Drug Enhanced version Mar 2019 C3). Medications will be 
presented by WHO Drug Anatomical/Therapeutic/Chemical category and Active 
ingredient.  
Summaries will be presented for prior and concomitant medications and procedures. 
All summaries will present the number and percentage of subjects for each 
medication/procedure.  
Prior and concomitant medication/procedures will be described as first excluding 
NSCLC treatment/procedures, then only the cancer treatment (e.g.: chemotherapy) or 
procedures (e.g.: radiotherapy or surgery) will be presented. 
The denominators for calculating the percentages will be based on the number of 
subjects in the ITT set.  
Summaries will be provided overall and by treatment group for ITT and Safety sets. 
All prior and concomitant medications/procedures presented in this section will be 
listed for patients in the ITT Set. 


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9.3.1. 
Prior/Concomitant 
Medications 
(excluding 
NSCLC 
treatment) 
Medications (excluding the NSCLC treatment) taken with an end date occurring before 
the first dose of study drug will be identified as prior medications.  
Medications (excluding the NSCLC treatment) taken with a start date occurring on or 
after the first dose date or medications taken with a start date prior to the first dose 
date and an end date on or after the first dose date and a start date before EOT date 
will be identified as concomitant medications.   
9.3.2. 
Prior/concomitant 
Procedures 
(excluding 
NSCLC 
treatment) 
Procedures (excluding the NSCLC treatment) performed with an end date occurring 
before the first dose of study drug will be identified as prior procedures.  
Procedures (excluding the NSCLC treatment) performed with a start date occurring on 
or after the first dose date or procedure performed with a start date prior to the first 
dose date and an end date on or after the first dose date and a start date before EOT 
date will be identified as concomitant procedures.   
9.3.3. 
Prior/Concomitant Cancer treatment  
Cancer treatment medications taken with an end date occurring before the first dose 
of study drug will be identified as prior cancer treatment.  
Cancer treatment medications taken with a start date occurring on or after the first dose 
date or medications taken with a start date prior to the first dose date and an end date 
on or after the first dose date and a start date before EOT date will be identified as 
concomitant cancer treatment.    
9.3.4. 
Prior/concomitant Radiotherapy/Surgery 
Procedures (considering only those for cancer treatment, e.g: radiotherapy/surgery) 
performed with an end date occurring before the first dose of study drug will be 
identified as prior procedures.  
Procedures (considering only those for cancer treatment, e.g: radiotherapy/surgery) 
performed with a start date occurring on or after the first dose date or procedure 
performed with a start date prior to the first dose date and an end date on or after the 
first dose date and a start date before EOT date will be identified as concomitant 
procedures.   
 
9.4. 
Treatment Compliance  
Compliance will be evaluated overall for the Safety Set, ITT Set and Per Protocol Set.  
Treatment compliance will be calculated as: 
Compliance (%) = (# tablets taken / # tables to be taken according to the study 
schedule).  
Where:  


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# tables taken = total number of tables taken between the date of first intake (included) 
and the date of last intake (included), as collected in the drug accountability CRF form. 
# tables to be taken according to the study schedule = date of Visit 10 - date of Visit 2 
+1. 
Date of Visit 10 will be replaced by the date of premature treatment discontinuation for 
patients who discontinued treatment prematurely. 
In case a patient completed the treatment but missed Visit 10 or in case a patient 
prematurely discontinued treatment and presented an EOT date, as recorded in the 
related CRF form, which is considered as implausible (i.e.: EOT date  greater than 25 
days after the date of the first dose of the last kit), then the corresponding Visit 10 date 
or EOT date will be replaced with the date of last visit performed + 24 days. 
If a subject returns all study medication that was dispensed, then the subject will not 
be classified as treated. 
In case of missing drug accountability data, it will be assumed that no tablets were 
taken for the corresponding days with missing data. 
For patients with kit(s) not returned, the information available in the drug administration 
CRF form about the documented tablet intake during the applicable study visit (i.e.: the 
study visit during which the first tablet from the kit – then never returned – was 
administered) will be used to add such one single day of documented treatment. For 
patients with kit(s) not returned and not having any information in the drug 
administration CRF form, i.e., there is no evidence that at least one tablet was taken, 
the number of tables taken will be assumed as 0. 
A patient will be considered compliant with the therapy if his/her overall compliance is 
higher or equal to 80%.  
Compliance will be reported numerically using descriptive statistics and categorically 
(using categories <80%, ≥80% to ≤100%, and >100%), by treatment group. 
 
 


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10. 
EFFICACY ANALYSIS 
All efficacy analyses will be performed on the ITT population.  
Some supportive analyses of the primary efficacy endpoints will be performed on 
different populations (FAS set and PP set). 
Unscheduled measurements and Visit 2 assessments done day(s) after the study 
treatment start date (therefore, not considered as baseline) will be excluded from the 
analysis and will be only listed.  
Descriptive statistics for all efficacy analyses will be performed both on actually 
observed data and after the imputation of the missing data. The inferential analyses 
will be produced only after the imputation of the missing data.  
Notably, for the purpose of the descriptive statistics (for both continuous and binary 
endpoints) after imputation of missing data, the average of the imputed and non-
imputed data over the N samples will be calculated. 
Details for the method of missing imputation are described in Appendix 12.1. 
Individual subject listings for all data (including both observed and means of imputed 
values) will be provided.   
 
10.1. 
Primary Efficacy Endpoints 
The two 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  
10.1.1. 
Primary efficacy endpoint derivation 
The mean change effect for both co-primary endpoints will be computed as sum of the 
changes from baseline over 12 weeks by the time of the last assessment (either week 
12 or before in case of death), 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 derivation of the 5 item Anorexia Symptom Subscale FAACT A/CS domain at 
each visit see Section 4.3.1 and Appendix 12.3. 
10.1.2. 
Primary efficacy analyses 
The primary efficacy analyses will be conducted on the ITT set. Statistical hypothesis 
H0w and H0a, as defined in Section 7.3, will be tested using an Analysis of Variance 
(ANOVA) model including treatment group and the three stratification factors at 
randomization as categorical covariates, at a Type-I error threshold of 0.05 two-sided.  
As anticipated in the beginning of this Section 10, inferential analysis will be done after 
imputation of missing data. An established number (N=100) of imputations will be 


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performed and for each of the imputation the ANOVA model will estimate treatment 
effect and the related standard error. The pooling of the estimates will be computed 
using the Rubin rule (1). The pooled effect and the related p-value will be interpreted 
for the primary efficacy analyses. In addition, the 95% confidence interval of the pooled 
difference and the least squares (LS)-mean with the 95% confidence interval will be 
presented per treatment group.  
More details for the multiple imputation process are described in Appendix 12.1.  
10.1.3. 
Sensitivity analyses 
The sensitivity analyses are aimed to confirm robustness of the conclusion of the 
primary efficacy analyses but are not part of the multiplicity adjustment.  
 Control-based imputation 
A sensitivity analysis regarding imputation of missing data will be performed using data 
from the placebo group only (control-based imputation) for all non-intermittent missing 
data. Therefore, the exceptions described in Appendix 12.1, deviating from the main 
control-based imputation, will not be taken into consideration.  
 Fluid retention replacement analysis 
As fluid retention may possibly influence the weight increase, a sensitivity analysis will 
be performed for the primary endpoint “Mean change in body weight from baseline 
over 12 weeks”, by considering as missing the values obtained in presence of fluid 
retention (for the definition of fluid retention, see Section 8.8 “Definitions”).  
Those missing values will be therefore imputed on the basis of the following rules for 
imputation: 
• In case of one or more body weight assessments measured in presence of fluid 
retention, comprised between two assessments (pre- and post-) measured in 
absence of fluid retention, the lower value between the assessed weight(s) and 
the weight(s) estimated by the linear interpolation between pre- and post-
assessments will be imputed.  
• If no subsequent values observed in absence of fluid retention are available, 
the post-baseline weight(s) recorded in presence of fluid retention will be 
imputed with the baseline value if that value is lower than the recorded value. 
Otherwise the recorded value will be used  
• If fluid retention is already present at baseline (due to protocol violation), 
no imputation will be performed and observed values will be analyzed. 
After imputation of these values, the imputation rule for the non-intermittent missing 
values described in Appendix 12.1 will be applied. 
Furthermore, an additional sensitivity analysis will be performed for the primary 
endpoint “Mean change in body weight from baseline over 12 weeks”, by excluding the 
patients for which fluid retention was reported at any time during the study. 


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 COVID-19 sensitivity analysis 
In case the subject was unwilling or unable to reach the research site or the site was 
not able to accommodate the visits during the COVID-19 pandemic, body weight was 
collected by the subject at home. Despite the recommendations to make the body 
weight data collection as most uniform as possible (8), high heterogeneity can be 
expected. This might possibly have an impact on the overall results. 
A sensitivity analysis will be performed for the primary endpoint “Mean change in body 
weight from baseline over 12 weeks”, by considering as missing the body weight values 
obtained when collected at home by the subject.  
Those missing values will be therefore imputed on the basis of the following rules for 
imputation: 
• In case of one or more intermittent missing value comprised between two 
assessments (pre- and post-) measured at site, the weight value(s) estimated 
by the linear interpolation between pre- and post-assessments will be imputed.  
• In case of no intermittent missingness (the weight values set at missing because 
collected at home during COVID-19 pandemic are the last ones and no other 
“post” assessment is performed at site) the imputation rule for the non-
intermittent missing values described in Appendix 12.1.1.2 will be applied with 
the following update: 
o All missing values (including also the weight values set at missing 
because collected at home) will be imputed assuming MNAR, specifically 
by means of the control-based multiple imputation method. 
o The exception 1, imputation of the missing values with the MAR 
approach under the circumstances described in Appendix 12.1.1.2, will 
be applied also on the subset of patients set at missing because collected 
at home 
 Mis-stratification sensitivity analysis 
During the course of the study and as part of the data and medical review process, 
some cases of mis-stratifications (i.e.: incorrect stratification information entered into 
the IRT system for the purpose of the randomization of the patients) were observed 
and investigated with the sites involved. The final list of mis-stratifications, confirmed 
by the PIs, was reviewed and discussed during the BDRM. 
Since the percentage of patients affected by such procedural deviations was about 
7,5%, even if any imbalance due to such randomization errors is expected to be 
minimal, a sensitivity analysis will be performed for the co-primary endpoint on the ITT 
set, using the correct strata information as part of the covariates included in the 
statistical model. Specifically, for the 5-item Anorexia Symptom Subscale stratum (≤10 
vs >10), the correct information is available in the clinical database (as part of the 
baseline assessments), while for the other two strata (systemic anti-cancer treatment 
line and cancer treatment), not being part of the clinical database variables, the correct 


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information to be incorporated into ADaM, displayed in the listings and used for the 
sensitivity analysis will be provided as external data, according to sites confirmation 
(see BDRM minutes and related attachment).  
10.1.4. 
Supportive analyses 
 Analyses on the FAS. 
Similarly to the primary efficacy analysis in the ITT set, the analyses will be conducted 
on the FAS set. 
 Analysis on the PP set 
Similarly to the primary efficacy analyses, the analyses will be conducted on the PP 
set. 
 Analysis on subgroups of the co-primary endpoint 
Similarly to the primary efficacy analyses, analyses will be conducted on the ITT Set 
based on the subgroups defined in Section 8.6. The statistical analyses and models 
will be based on the models used for the co-primary endpoints described in Section 
10.1.2.  
A forest plot presenting point estimates and 95% confidence intervals will be presented 
for weight and 5-IASS. 
 Premature discontinuation and retrieved dropouts 
In order to summarize the presence of retrieved dropouts in the data of body weight 
and 5-IASS, a frequencies for patients who have the last efficacy assessment at the 
same week as the last treatment given as well as retrieved dropouts patients will be 
calculated. The number and percentage of patients will be presented for each 
category, including a sub-category of patients who have the last efficacy assessment 
at the same week as the last treatment given and who stayed alive during the study. 
Summaries will be done separately for body weight and for 5-IASS by treatment arm 
on the ITT set.   
 
10.2. 
Secondary Efficacy Endpoints 
All the analyses of the secondary endpoints will be conducted on the ITT set.  
The following secondary endpoints are to be analyzed: 
• Duration of treatment benefit in body weight (≥0 kg) over 12 weeks 
• Duration of treatment benefit in body weight (≥ 1.5 kg) over 12 weeks 
• Duration of treatment benefit in 5-item Anorexia Symptom Subscale (≥0 points) 
over 12 weeks 


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• Duration of treatment benefit in 5-item Anorexia Symptom Subscale (≥ 3 points 
improvement) over 12 weeks 
• Mean change in FAACT 12-item A/CS domain score 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 
As described in Section 7.3 the secondary efficacy endpoints analyses will be 
performed by following a hierarchical order.  
Subgroup analysis for the secondary endpoints, are defined in Section 8.6.  
10.2.1. 
Secondary efficacy endpoints derivation 
Secondary endpoints based on Duration of treatment benefit 
The duration of treatment benefit over 12 weeks is not directly collected in the study 
data but should be derived from: 
- 
the dates of the assessments (either observed or imputed),  
- 
the values of the assessments (either observed or imputed)  
The duration of treatment benefit over 12 weeks is measured as the period, or the sum 
of the periods, over 12 weeks (or less in case of death), in which the patient observed 
a change from baseline superior or equal to the threshold.  
For the purpose of computation, it will be assumed a linear evolution between two 
measurements. 
Below some examples (threshold = 0. Same approach in case of threshold=clinical 
meaningfulness) 
 
 


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Case 1: benefit all over 12 weeks. No need of linear interpolation 
 
Duration of treatment benefit = Date of Week 12 – Date of Baseline assessment 
Case 2: benefit until a given visit. Need of linear interpolation 
 
In case 2 the algorithm should estimate the time when the line between two 
measurements (in the example between Week 9 and Week 12) crosses the threshold. 
The equation of the line passing through two given points: (x1, y1) and (x2, y2) is the 
following: 
 (Y -Y1)/(Y2-Y1) = (X-X1) / (X2-X1) 
Where Y=0 if the threshold=0 (or =clinical meaningfulness threshold, otherwise) and: 
X1=date of the Visit at Week 9 
0
0.5
1
1.5
2
2.5
0
3
6
9
12
change from baseline
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
2
2.5
0
3
6
9
12
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Y1=value of assessment (e.g., Body Weight) at Week 9 
X2=date of the Visit at Week 12 
Y1=value of assessment (e.g., Body Weight) at Week 12 
Setting Y=0 (threshold value), the equation estimates the time XT when the benefit 
ends. 
The duration of benefit will be = (Date of Week 9 – Date of Baseline assessment) + 
(Date of XT – Date of Week 9). 
Case 3: intermittent benefit. Need of linear interpolation 
 
 
For case 3 estimation of duration of benefit follows the same approach as for Case 2. 
These examples describe cases with all assessments available (e.g.; after multiple 
imputation).  
The same approach will be applied to derive the endpoints before the multiple 
imputation (observed values, to be presented as descriptive statistics). 
If treatment benefit is not reached, the duration of treatment benefit in this patient will 
be set to 0; these patients will be included into the statistical analysis. 
Secondary endpoints based on Mean Change from baseline over 12 weeks 
The mean change effect for these secondary endpoints will be computed as sum 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). This is aligned to the approach followed for the main analysis of the 
co-primary endpoints. 
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
1.5
0
3
6
9
12
change from baseline


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10.2.2. 
Secondary efficacy endpoints analyses 
All secondary endpoints (duration of treatment benefit over 12 weeks and mean 
change from baseline over 12 weeks in FAACT-F 12-items, FACIT-F and FAACT total 
score in the secondary efficacy endpoints) will be analyzed using the same statistical 
model and multiple imputation approach as for the co-primary efficacy endpoints. 
Details are reported in Section 10.1.2 and Appendix12.1. 
10.2.3. 
Secondary efficacy analysis on subgroups 
For all secondary efficacy endpoints, analyses will be conducted on the ITT Set based 
on the subgroups defined in Section 8.6. The statistical analyses and models will be 
based on the models used for the secondary endpoints described in Section  10.2.2. 
For subgroups defined based on a stratification factors, the corresponding variable will 
be excluded from the model for the analysis. 
Forest plots will be done presenting point estimates and 95% confidence intervals of 
each secondary efficacy endpoints. 
 
10.3. 
Exploratory Endpoints 
All the analyses of the exploratory endpoints will be conducted on the ITT. See Section 
6.1.3 for the list of exploratory endpoints which will be analyzed. 
The datasets imputed for the primary and secondary efficacy endpoints will be used 
also for the analysis of the exploratory endpoints. 
10.3.1. 
Exploratory endpoints derivation. 
All the rules defined for the derivation of the primary and secondary endpoints apply to 
the exploratory endpoints as relevant. 
 Mean Change from baseline over X Weeks  
Mean Change in Body Weight, in 5-IASS and in FAACT total score from baseline over 
6, 9, 15, 18, 21, and 24 Weeks are derived as the primary efficacy endpoint (see 
Section 10.1.1). 
For instance: 
Mean change in Body Weight from baseline over 24 Weeks is calculated as the sum 
of the changes from baseline over 24 weeks by the time of the last assessment (either 
week 24 or before in case of death), and then divided by the number of assessments 
(observed or imputed) from baseline up to the time of the last assessment (either week 
24 or before, in case of death).  
 Percentage of Change in Body Weight  
Percentage of change in body weight from baseline computed as 
 (Weight at Visit – Baseline) / Baseline * 100 


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 Composite Clinical Response (CCR)  
CCR is a composite measure defined as: 
o 1.5 kg body weight gain from baseline and  
o ≥ 3 points gain in the 5-item Anorexia Symptom Subscale score from 
baseline. 
The two components of CCR are derived as follows: 
o Achievement of 1.5 kg gain in body weight from baseline computed as 
▪  If change in body weight ≥ 1.5 kg then “Responder”; 
 otherwise “Non-responder” 
o Achievement of ≥ 3 points increase in 5 I-ASS from baseline computed 
as 
▪ If (5-IASS at Visit - Baseline) ≥ 3 then “Responder”;  
otherwise “Non-responder” 
 
CCR is then computed as  
o If “Responder” in Achievement of ≥ 1.5 kg gain in body weight, and 
If “Responder” in Achievement of ≥ 3 points increase in 5-IASS, and  
If patient is alive then “Responder”; 
otherwise “Non-responder” 
 Achievement of responder threshold 
At each visit: 
- 
“Responder” if value >= clinically meaningful threshold and patient is alive 
- 
“Non-responder” otherwise 
Definition of Clinically meaningful threshold is given in Section 8.8. 
 Change from baseline 
Changes from baseline to Weeks 3, 6, 9, 12, 15, 18, 21, and 24 are derived as: 
(“variable” at Visit – Baseline).  
10.3.2. 
Exploratory endpoints analyses. 
The exploratory efficacy analyses are aimed to explore the effect of the anamorelin on 
different endpoints but are not part of the Type I error multiplicity adjustment, thus have 
no confirmatory value. 
 Mean Change from baseline over X Weeks 
The exploratory endpoints based on the “mean change from baseline over X Weeks” 
will be computed and analyzed like the main analysis for the primary efficacy 
endpoints.  


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 Change from baseline 
All the exploratory endpoints based on the “change from baseline” 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.  
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 
dataset and pooled using Rubin’s method (1). 
 Responder Analysis (CCR and Achievement of 
responder threshold) 
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. Frequency and rate of responders will be 
reported with Clopper-Person 95% confidence intervals (CIs). For the treatment 
comparison, the odds ratio will be reported with 95% CI. Statistics will be evaluated in 
each imputed dataset and pooled using Rubin’s method (1). 
 Correlations and scatter plots 
To explore the correlation between the weight gain and the improvement on the patient 
reported anorexia score, the Pearson’s correlation coefficient between change from 
baseline in Body Weight and change from baseline in 5-item Anorexia Symptom 
Subscale respectively will be estimated overall and within each treatment group. 
Analysis will be performed at each Study Visit. Same analysis will be performed using 
the mean change over 12 weeks. 
In addition, a scatter plot of the change from baseline of the two variables will be 
presented (change from baseline in Body Weight at Y-axis and change from baseline 
in 5-IASS at X-axis), with a display of the distribution of each single variable. The 
analysis will be performed at each Study Visit. Same analysis will be performed using 
the mean change over 12 weeks. 
Correlation and Scatter plot will be performed both on observed data and after 
imputation. 
 PGIS, PGIC and Hunger assessment 
The PGIS and the PGIC endpoints and the hunger assessment will not be imputed, 
only observed value will be summarized. PGIS and PGIC are aimed to identify the 
responder threshold in the 5-IASS and weight. The related statistical analyses is 
reported separately (6, 7). 


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 Change from baseline to Week 12 in body weight 
(categorical) 
Additionally, absolute change from baseline in body weight to Week 12 will be 
categorized as follows:  
• <-3 kg 
• < -2 kg to >= -3 kg 
• < -1 kg to >= -2 kg 
• <= 0 kg to >= -1 kg 
• > 0 kg to <= 1 kg 
• > 1 kg to <= 2 kg 
• > 2 kg to <= 3 kg 
• > 3 kg. 
Summary will present the number and percentage of subjects for each body weight 
category by treatment. 
 
 


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11. 
Safety Analysis 
All safety analyses will be performed on the Safety set.  
 
11.1. 
Exposure 
Duration of overall exposure (days) will be calculated as the difference between last 
tablet intake date and the first tablet intake date plus 1. 
• Duration of overall exposure (days) = date of EOT - date first tablet intake +1 
Duration of overall exposure will also be calculated in weeks using the following 
formula: 
• Duration of overall exposure (weeks) = Duration of exposure (days) / 7 
Duration of overall exposure, as defined above, will include any period of temporary 
treatment interruption.  
The duration of overall exposure in days will be summarized using descriptive statistics 
by treatment groups. 
A contingency table by treatment groups will also be presented with the following 3-
weeks categories:  
• [0-3) 
• [3-6) 
• [6-9 
• [9-12) 
• [12-15) 
• [15-18) 
• [18-21) 
• [21-24) 
• ≥24 weeks. 
In addition, duration of actual exposure (in days and weeks respectively) will be also 
calculated similarly to the duration of overall exposure but removing any treatment 
interruption (i.e.: considering actual differences between dates of last and first tablet 
intake as reported in the drug accountability for each drug kit returned). 
In case a patient prematurely discontinued treatment and presented an EOT date, as 
recorded in the related CRF form, which is considered as implausible (i.e.: EOT date 
greater than 25 days after the date of the first dose of the last kit), then for calculation 
of actual exposure the corresponding EOT date will be replaced with the date of last 
visit performed + 24 days. 
For patients with  kit(s) not returned but with information available in the drug 
administration CRF form about the documented tablet intake during the applicable 
study visit (i.e.: the study visit during which the first tablet from the kit – then never 
returned – was administered), this will be used to estimate the date of last intake from 
the kit, adding 24 days (as maximum number of tablets available in the kit to be 


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regularly taken) after the first intake. This approximation will be done to derive 
treatment interruptions for kit(s) that were not returned. This is applicable for actual 
exposure calculation only. 
Exposure data will be listed for all subjects in the Safety Set. 
 
11.2. 
Adverse Events  
AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary (version 22.0) to assign a preferred term (PT) and a system organ class 
(SOC) for each event.  
11.2.1. 
Classification of Adverse Events 
The reporting period for AEs is the period starting from the date/time of Informed 
Consent signature and lasting until Visit 11 (approximately 183 (+3) days post study 
drug administration on Day 1). All AEs (including SAEs) occurring within this period 
and not resolved by the end of the period will be documented on the eCRF as 
“ongoing”. 
Pre-Treatment AEs 
An AE with onset date between date/time of Informed consent and the date of the first 
dose of the study drug (not included) is classified as a pre-treatment AE: 
• 
Pre-treatment AE: AE onset date < date of the first dose of study drug; 
Treatment-Emergent AEs 
A treatment-emergent AE (TEAE) is an AE with onset date on or after the date of the 
first dose of the study drug and up to Study completion (last study visit being Visit 11: 
approximately Day 183 +3 days after first dose). 
• 
TEAE: date of the first dose of study drug ≤ AE onset date ≤ date of completion 
In case of treatment discontinuation an AE is classified as TEAE if: 
• 
TEAE: date of the first dose of study drug ≤ AE onset date ≤ date of 
discontinuation +14 days 
Notes:  
- 
Events where the onset date is the same as the study drug start date are assumed to 
be TEAEs; 
- 
By protocol 14 days is the post-treatment time-window for completers between Visit 10 
(last dose) and Visit 11 (follow-up by phone call). 
Any AE already present before the first dose of the study drug, that worsens in either 
intensity or frequency following exposure to the treatments is to be considered as new 
event classified as TEAE. 
Post-Study AEs 


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All AEs fulfilling the following conditions: 
- 
onset date > study completion or 
- 
onset date > treatment discontinuation+14 days 
are classified as post-study AE. 
In case of missing or incomplete dates not directly allowing allocation to any of the 
three categories of AEs, see the rules defined in Section 8.3.5. 
Pre-treatment AEs, TEAEs and post-study AEs will be presented separately. Summary 
tables will be provided on TEAE only. Pre-treatment AEs and post-study AEs will be 
presented in the listings only. 
11.2.2. 
Adverse Events of Special Interest (AESI) 
Adverse events of Special Interest are pre-specified as the following (PTs): 
1. 
Aspartate aminotransferase increase (CTCAE Grade ≥ 3) 
2. 
Alanine aminotransferase increase (CTCAE Grade ≥ 3) 
3. 
Presyncope (any CTCAE Grade) 
4. 
Syncope (any CTCAE Grade) 
5. 
Ventricular arrhythmia (CTCAE Grade ≥ 3) 
6. 
Cardiac failure (CTCAE Grade ≥ 3) 
7. 
Sudden death 
8. 
Seizure (any CTCAE Grade) 
9. 
Hyperglycemia (CTCAE Grade ≥ 3) 
11.2.3. 
Summaries of Adverse Events 
A summary table reporting the total number of events, the total number of patients and 
the percentage of patients experiencing at least one of the following: 
▪ Treatment-emergent adverse events (TEAEs) 
▪ Drug-related TEAEs  
▪ Serious TEAEs (SAEs) 
▪ Drug-related SAEs  
▪ TEAE CTCAE ≥ grade 3. 
▪ TEAEs leading to treatment discontinuation  
▪ Drug-related TEAEs leading to treatment discontinuation, 
▪ Treatment-emergent AEs of special interest 
▪ AEs with outcome Deaths 
will be created by treatment group. 
Drug-related TEAE are defined as AEs with relationship classified by the investigator 
as definitely, probably, possibly, unassessable or missing. 
Each of the categories reported above will also be summarized in separate tables by 
SOC and PT: 
▪ By decreasing frequency for SOC;  


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▪ By decreasing frequency for PT within the SOC;  
Each summary table will be created by treatment group and overall. 
For all adverse events, data will be prepared classifying events using MedDRA 
dictionary with respect to preferred term and SOC by treatment group.  
Patients will be counted only once at the SOC level and will be counted once for each 
applicable preferred term; the total number of events will be presented for each 
SOC/PT.  
11.2.4. 
Summaries of Adverse Events by Maximum CTC grade 
Severity 
At individual patient level, the maximum CTC grade describes the worst grade 
experienced by a patient at any point in the treatment, irrespective to the AEs. 
At a SOC/PT level, if a subject has multiple AEs with same preferred term the 
maximum CTC grade for that PT is used in the analysis. 
If an AE has no grading, grade 3 is assigned; grade 4 or 5 will be assigned only if life-
threatening consequence or death respectively will be observed. 
A summary of maximum CTCAE grade at patient level will be reported by treatment 
group. The incidence of TEAEs in each treatment arm will also be presented by SOC 
and PT. For each PT the grouping by severity according to the CTCAE grade 
(maximum grade in case of multiple AEs with same preferred term) will be reported. 
11.2.5. 
Summaries of Adverse Events by Maximum relationship 
to the study treatment 
At individual patient level the highest level of relationship experienced by a patient at 
any point in the treatment, irrespective to the AEs, will be presented. 
For summaries presenting AEs related to study drug, the number of patients with an 
AE, is the number of patients who have each level of relationship as the highest level 
of relationship for the specific PT. 
11.2.6. 
Summaries of TEAEs of Special Interest 
A table presenting details of the Treatment-emergent AEs of special interest will be 
provided by treatment arm. TEAESI will be also listed separately. 
 
11.3. 
Laboratory Data  
For continuous clinical laboratory results (hematology and biochemistry parameters), 
the absolute value and change from baseline will be summarized by parameter and 
visit using descriptive statistics for the Safety Set. For laboratory parameters where the 
shifts to the last assessed value are evaluated, change from baseline to the last value 
assessed will be summarized as well. 


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If the value is below the lower limit of quantification (e.g.: “< X.X”), then half the lower 
limit of quantification will be used in the summary tables to calculate the descriptive 
statistics. If the value is above the upper limit of quantification (e.g.: (e.g.: “> X.X”), then 
the upper limit of quantification will be used in the summary tables to calculate the 
descriptive statistics. In the listings, values will be listed as collected without the 
imputation applied. 
Shift tables from baseline to the Last Value according to NCI CTCAE V5.0 grade 
(published on Nov 2017) will be provided for selected chemistry parameters (ALT, AST, 
total bilirubin, ALP, creatinine, and glucose) and hematology parameters (hemoglobin, 
platelet count, white blood cells, and neutrophils).   
Frequency tables according to NCI CTCAE worst grade over time will be provided for 
ALT and AST. 
In addition, % change from baseline by visit will also be measured for HbA1c and pre-
albumin. 
Urinalysis 
Urinalysis parameters (WBC, Erythrocytes, Protein, Glucose and Bacteria) will be 
classified as normal or abnormal and will be summarized by parameter using the 
number and percentage of subjects in each category for the Safety Set.  
Shift tables from baseline to the Post-baseline Values will be presented. For WBC and 
Erythrocytes, values classified as High or Low will be recoded to Abnormal to be 
presented using the same layout as for the other qualitative urinalysis parameters. 
All clinical laboratory data will be listed, and values outside the normal ranges will be 
flagged. 
All clinical laboratory values, abnormal clinical laboratory values, and clinically 
significant laboratory values (including data collected at any unscheduled 
assessments) will also be provided in data listings. 
Pregnancy test 
The results of pregnancy test by visit will be summarized with counts and percentages 
of patients by treatment in the ITT Set. 
 
11.4. 
Vital Signs  
Vital sign measurements for the Safety Set will be summarized using descriptive 
statistics by visit. The change from baseline will also be summarized in the same 
manner. Unscheduled vital signs assessments will be excluded from the tables. 
All vital signs, weight and BMI measurements will be listed in the ITT Set including data 
collected at any unscheduled assessments. 
In principle, any treatment emergent clinically significant change in vital signs will be 
reported as an AE. 


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11.5. 
Electrocardiogram (ECG) 
Shift tables from baseline to the worst post-baseline results will be provided for the 
ECG overall interpretation. The following categories will be used: normal, abnormal 
and not clinically significant, abnormal and clinically significant. The frequencies of 
ECG overall interpretation by visit as well as the number and percentage of patients 
who performed the assessment will be also tabulated. 
ECG measurements (HR, QT, QTcF, QTcB, PR, RR, and QRS) will be summarized 
using descriptive statistics by treatment group and visit. The change from baseline will 
also be summarized in the same manner.12-lead ECGs measurements are obtained 
in triplicate. Analysis will be performed using the average of the three measurements. 
In case of one or two measurements are missing the average will be calculated on the 
bases of the available measurements. Summaries showing the number and percent of 
patients with outlier values will be presented by treatment.  
Outlier values will be identified using the following criteria: 
 
Any treatment emergent clinically significant ECG abnormality will be reported as an 
AE. 
All ECG data will be listed by patient. 
 
11.6. 
Physical Examination 
Any treatment emergent clinically significant physical examination abnormality will be 
reported as an AE.  Physical examination findings will be listed.  
The signs and symptoms of edema will be tabulated by visit and treatment. 
 
11.7. 
ECOG Performance Status 
ECOG performance status will be summarized using shift tables from baseline 
(Screening) to Week 9. 
 
ECG interval 
Categorical outlier criteria 
QTcF 
Treatment-emergent value of > 450 and ≤ 480 ms when not present at baseline (new onset) 
Treatment-emergent value of > 480 and ≤ 500 ms when not present at baseline (new onset) 
Treatment-emergent value of > 500 ms when not present at baseline (new onset) 
Increase of QTcF from baseline of > 30 and ≤ 60 ms 
Increase of QTcF from baseline > 60 ms 
PR 
Increase of PR from baseline > 25% resulting in PR > 200 ms 
QRS 
Increase of QRS from baseline > 25% resulting in QRS > 120 ms 
HR 
Decrease of HR from baseline >25% resulting in HR < 50 bpm 
Increase of HR from baseline >25% resulting in HR > 100 bpm 


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11.8. 
Overall Survival 
Overall survival for the two treatment arms will be analyzed descriptively using Kaplan-
Meier estimation. Efron method will be implemented for handling ties. Descriptive 
statistics will be provided as median time to event (and Interquartile Range). A 
summary of events and censored subjects will be given for each arm (n, %). K-M Plot 
with the survival curves for the two treatment arms will also be provided. 
The difference in survival between anamorelin and placebo, descriptively assessed 
using a stratified Cox regression analysis (stratified by stratification factors listed in 
Section 8.4), will be provided as estimate of hazard ratio (HR) and 95%CIs.  
Event or censor time in weeks will be calculated as follows: 
• Event time (i.e. death) = ([date of death] – [Study Treatment Start Date] +1 
day)/7 
• Event time (i.e. no death) = ([last follow-up contact date – [Study Treatment 
Start Date] +1 day)/7 
In this derivation, “Study Treatment Start date” instead of “Randomization date* is used 
because Overall Survival is considered as Safety variable. 
 
11.9. 
Tumor Assessments 
Change in tumor assessment at the latest CT scan performed during the treatment 
period compared to CT scan at baseline (overall response categorized into complete 
response, partial response, stable disease and progressive disease) will be 
summarized by treatment group with frequencies and percentages. 
Baseline CT scan is performed at screening visit or within 28 days of the first dose of 
study drug.  
All patients at all sites will perform CT scans as per standard local practice and 
responses evaluated according to the RECIST 1.1. Description of target and non-target 
lesions as well as overall response before randomization (if any) will be provide as 
listing. 


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12. 
APPENDICES 
 
12.1. 
Missing value imputation process 
Imputation of missing values will be performed following: 
- 
the multiple imputation (MI) method for missing data, based on the approach 
described in literature by Ratitch (1, 2).  
- 
Single imputation method, which is described, case by case, in the process 
reported below. 
Conventions: 
- 
All observed data will be included in any analysis; 
- 
The missing data of the variables being part of the primary efficacy endpoints 
(body weight, 5-item Anorexia Symptom Subscale score) and the 
secondary/exploratory efficacy endpoints will be imputed;  
- 
A specific sensitivity analysis for the primary efficacy endpoint “Mean change in 
body weight from baseline over 12 weeks" will be performed to replace the body 
weight value of the patients with fluid retention at the date of the assessment. 
These values will be firstly set to missing and, then, imputed with the imputation 
approach reported in Section 10.1.3.2. 
- 
No imputation will be performed for survival status and no data will be imputed 
after patient death. 
When a measurement will be missing for patients who are alive, the imputation will 
depend on the pattern of missingness: non-monotone vs. monotone: 
- 
In case of non-monotone pattern, missing values may occur in the middle of a 
subject record (e.g., missed intermediate visit). These are also called 
“Intermittent missing values”. 
- 
In case of a monotone pattern, it is possible to arrange variables so that, for all 
subjects, missing values are always located in a block at the end of data records 
(e.g., due to study discontinuation). These are also called “non-Intermittent 
missing values”.  
For the definition see also Section 8.8. 
12.1.1. 
Imputation rules 
 Imputation for Intermittent missing values (non-
monotonic missingness) 
These 
values 
will 
be 
imputed 
with 
the 
value 
obtained 
by 
linear 
interpolation between prior and post values.  


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 Imputation rules for Non-intermittent missing values 
(monotonic missingness) 
Imputation rules for non-intermittent missing values are based on a main rule and some 
exceptions.  
The rule and the exceptions will be applied separately for each efficacy parameter. 
Main rule  
All missing values will be imputed assuming MNAR, specifically by means of the 
control-based multiple imputation method. 
Reason: Most of the patients are expected to have missing values from time of 
treatment stop. In addition, the patients under study are characterized by poor 
prognosis and the reasons for treatment discontinuation are expected to be more 
related to the background disease than to treatment failure. For this reason, it cannot 
be assumed that the values after the treatment discontinuation would follow the same 
trend as before discontinuation because the general conditions, with specific 
exceptions described below, after discontinuation get to worsen. The implementation 
of the control-based imputation is conservative because it assumes that the 
deterioration of the patient condition affects mainly the patients in the active treatment 
group.  
Exceptions 
1. Independent from reason for discontinuation of treatment, if: 
o at least two non-missing post-baseline assessments are available (first assessment = 
X1 and last assessment = Xlast) and, 
o Xlast - X1 ≥0 and Xlast ≥baseline,  
then impute all the missing values with the MAR multiple imputation approach 
including randomised treatment as the covariate. 
2. If reason for discontinuation of treatment = “Physician decision” or = “Withdrawal 
by subjects” and: 
o at least two non-missing post-baseline assessments are available (first assessment = 
X1 and last assessment = Xlast) and,  
o Xlast - X1 <0 and Xlast <baseline,   
then impute all missing values to the worst value observed for the subject, 
considering only the on-treatment (post-baseline) timepoints. 
Reasons: 
Imputation for Exception 1 
This exception is applicable for any reason for discontinuation, when the trend reveals 
an improvement of the efficacy assessments over time, with the last post-baseline 
assessment (Xlast) better than both the baseline and the first post-baseline assessment 
(X1). Based on these conditions, it is assumed that the decision of stopping the 
treatment is not related to the treatment itself (since the efficacy parameter was 
improving over time). Due to the improvement over time, it can also be assumed that 


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the treatment effect would have been maintained as it was before interruption for the 
rest of the observation period. For this reason, the missing values after the treatment 
discontinuation will be imputed with the Missing at Random (MAR) multiple imputation 
approach including randomized treatment as the covariate. This approach might be 
slightly optimistic for values missing at visits far from the visit of the last assessment, 
however this will not impact the primary endpoint that is limited to week 12, considering 
that at least assessments at week 3 and at week 6 are requested by the rule. 
Imputation for Exception 2 
This exception is limited to the reasons of treatment discontinuation that are most likely 
related to lack of efficacy of the treatment; the criterion for considering the unknown 
values as related to lack of efficacy is the negative trend of the observed efficacy 
assessments over time, as documented by the last post-baseline assessment (Xlast) 
worse than the baseline and the first post-baseline assessment (X1). Based on these 
conditions, it is assumed that the decision of stopping the treatment can be related to 
the treatment itself (lack of efficacy). The missing values will be imputed with the worst 
value observed for the patient considering only the on-treatment (post-baseline) 
timepoints.  
Final revision of the above rules was done at the BDRM and they have been 
confirmed.  
The details of the process are showed in the following steps.  
STEP 1: Single/Multiple imputations 
- 
Impute all intermittent missing data 
- 
Create 100 records for each value 
- 
Application of the Main Rule:  
Apply MNAR Control-Based imputation on all subjects (placebo and active 
treatment) with at least one missing assessment. 
- MI on all non-intermittent missing 
- only placebo patients contribute to the imputation. 
Expectation after imputation: only 1 dataset including: 
o ANAM and placebo patients without missing data (all assessments observed) 
o ANAM and placebo patients with at least 1 missing assessment imputed by the 
imputation process.  
Note: it is theoretically possible that aberrant values are derived because of the 
imputation. Aberrant values are defined as follows: 
o For each item of the questionnaires:  
a) Imputed value < the lower limit (0) 
b) Imputed value > the upper limit (4) 
o For the body weight:  
a) Imputed value < the lower limit (30 Kg) 
b) No upper limit for the Body Weight is fixed. 


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In the cases (a) the imputed value will be set equal to the lower value. 
In the cases (b) the imputed value will be set equal to the upper value. 
Unscheduled assessments of body weight and questionnaires are not considered for 
imputations. These values will be listed only (and have all ANL0XFLs set to blank). 
- 
Application of Exception 1:  
Apply MAR (as correction to the previous control-based imputation on patients 
fulfilling Exception 1)  
Note: Values to be imputed with MAR need first to be re-set at missing. 
A flag before starting with the imputation process should identify the cases 
where the exception 1 should be applied. 
Imputed values after MAR imputation should be within the aberrant values 
described above for the MNAR imputation 
- 
According to Exception 2:  
Impute worst value at subject level.  
A flag before starting with the imputation process should identify the cases 
where the exception 2 should be applied. Worst value should be calculated 
before any imputation. 
- 
The imputation process does not distinguish between missing due to 
treatment discontinuation and death. All imputed assessments after death 
must be set to missing. 
No covariates, apart from treatment arm (as by variable or covariate, as relevant) and 
baseline value will be included in the MI models. 
For each variable, 100 imputed values will replace each missing value. 
The following variables will be separately imputed according to the above mentioned 
single or multiple imputation methods: 
- Weight 
- 5-IASS 
- 4-item Anorexia Concerns Subscale (4-IACS) 
- 12-item A/CS domain 
- FAACT total score 
- FACT-G total score 
- FAACT TOI 
- Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) 
- FACIT-F TOI score 
The PGIS and the PGIC endpoints and the hunger assessment will not be imputed. 
Once the imputation process is complete, the dataset will contain the observed values 
and the imputed values.  


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All the values imputed after the intercurrent event death and set to missing, in respect 
to the “while-alive” principle will be considered as non-responders in the “responder 
analyses”.  
The value of the derived endpoints (e.g.: mean change, duration of benefit, change 
from baseline) will be computed once the imputation datasets are created. 
STEP 2: Perform the relevant analyses. 
Each of the imputed datasets for primary/secondary/exploratory efficacy endpoints will 
be analyzed separately using the method declared in the proper section (for instance, 
the primary efficacy analysis, see Section 10.1.2, will be based on an ANOVA model 
to compare the two treatment groups, at a Type-I error threshold of 0.05 two-sided). 
Each model will provide an estimate of the treatment effect and of the related standard 
error. 
STEP 3: Combine Parameter Estimates. 
The pooling of the estimates will be computed using the Rubin rule (1). The pooled 
effect 
and 
the 
related 
p-value 
will 
be 
interpreted 
for 
the 
primary 
(secondary/exploratory) efficacy analyses.  
 
12.2. 
Statistical Software 
Statistical analyses will be performed using SAS Version 9.4 (or higher) for Windows. 
The SAS procedures and data steps presented below are only examples of the 
procedures to be implemented. 
The SEEDS are the ones to be used in the procedures. 
12.2.1. 
Single/Multiple imputation 
Notes: 
▪ 
Intermittent missing data are imputed by linear interpolation, single 
imputation 
▪ 
N=100 imputation samples (variable “_IMPUTATION_”) are created prior to next 
step (PROC MI) 
▪ 
TRTPN=’0’: refers to placebo treatment arm 
 Placebo (control-based) imputation 
 
PROC MI DATA=DATA1 SEED=191124 OUT=DATA2A NIMPUTE=1; 
 
BY _IMPUTATION_ ; 
CLASS TRTPN; 
 
VAR W_00 &VARS;  
 
MONOTONE REGRESSION; 
MNAR MODEL(&VARS 
/ modelobs= (TRTPN=’0’)); 
RUN; 
 


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Macrovariable &VARS includes W_03 for imputing data at visit 3 weeks, includes 
W_03 and W_06 for imputing data at visit 6 weeks, and so on. 
 
Note: No “Where” clause is used. The model processes ALL records. For the records without any missing data the model 
does not apply any action.  
 MAR imputation 
 
PROC MI DATA=DATA1 SEED=458122 OUT=DATA2B  NIMPUTE=1; 
 
BY _IMPUTATION; 
CLASS TRTPN; 
 
VAR TRTPN W_00 W_03 W_06 W_09 W_12 W_15 W_18 W_21 W_24;  
 
MONOTONE REGRESSION; 
RUN; 
 
Note: DATA2B dataset derives from DATA2A (see output dataset from MNAR placebo control-based imputation) after 
re-setting at missing the assessments as per Exception 1 (see above) 
 Worst value imputation 
 
DATA DATAx ; SET DATAx; 
Where &sel; 
<<identification of the worst value (WORST) for the subject where: 
At least 2 non-missing: 
Xlast<X1 
Xlast<baseline >> 
Run; 
 
Data Datax2; 
Set datax; 
if W_09=. then W_09=WORST; 
if W_12=. then W_12=WORST; 
if W_15=. then W_15=WORST; 
if W_18=. then W_18=WORST; 
if W_21=. then W_21=WORST; 
if W_24=. then W_24=WORST; 
RUN; 
 
&sel = selection of reason for discontinuation in (“withdrawal by subject”, “physician 
decision”) 
 Combining the imputations 
Imputations will follow the sequence as specified in Section 12.1.1.2. 
Values imputed after a patient died will be re-set to missing (which guarantees to have 
no response after death, as a missing value in SAS is below any value, including the 
threshold). 
Imputed values that are outside the range of the parameter will be set to the relevant 
limit of the range. 


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12.2.2. 
Data Analysis 
Each of the imputations will be analyzed by usual SAS procedure. 
For the primary efficacy analyses and for the other analyses based on ANOVA, the 
pooling will be done as follows: 
 
/** Model by imputation **/ 
proc mixed data=[imputed dataset] ; 
by  _IMPUTATION_ ; 
class TRTPN(ref="0") [classCovariates]; 
model meanchange_w = [COVARIATES] TRTPN ; 
lsmeans TRTPN / cl diffs ; 
 
estimate 'Anamorelin - Placebo' trtpn 1-1 /cl; 
ods output LSMEANS=MIlsmeans; 
ods output estimates=MIancova; 
run ; 
12.2.3. 
Pooling of the analysis 
The results of the analysis will be summarized with SAS ® PROC MIANALYZE.  
 
/** perform the pooling **/ 
proc mianalyze data= MIancova all ; 
modeleffects estimate ; 
stderr stderr ; 
ods output parameterestimates= ANCOVADIFFS_OUT; 
run ; 
 
The output dataset MIlsmeans can be used to obtain the LSmeans by treatment, 
by using the relevant proc myanalyze, as follows: 
 
proc sort data=MIlsmeans; by trtpn;      where effect='trtpn'; run; 
proc mianalyze data=MIlsmeans_&var.; 
    modeleffects Estimate ; 
    stderr stderr ; 
    ods output parameterestimates=ANCOVAls; 
 
  by trtpn;  
run; 
 
For the Responder analyses the following approach will be implemented. 
 
 
*From Ratitch's paper 'Combining Analysis Results from Multiply 
Imputed Categorical Data' PharmaSUG 2013 - Paper SP03; 
 
***Log-transform odds ratio estimates; 
 
 data lgodds_t; 
 
    set lgodds (where=(index(effect,"TREATMENT"))); 
 
 
or_lg=log(oddsratioest); 
 
 
or_lg_se   =(log(uppercl)-log(lowercl))/(2*1.96); 
 
run; 
 
 
***Combine transformed estimates; 
 
PROC MIANALYZE DATA=lgodds_t; 
 
  ods output parameterestimates=or_lg; 


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  modeleffects or_lg; 
 
  stderr       or_lg_se; 
 
run; 
 
 
***Back-transform combined values; 
 
data or; 
 
  set or_lg; 
 
  OR_pool  =EXP(ESTIMATE);             *Pooled Odds Ratio; 
 
  OR_pool_L=OR_pool*EXP(-1.96*STDERR); *Pooled lower limit; 
 
  OR_pool_U=OR_pool*EXP( 1.96*STDERR); *Pooled lower limit; 
 
run; 
 
12.3. 
Questionnaires scoring guidelines 
 
FAACT Scoring Guidelines (Version 4) – Page 1 
 
Instructions:* 
1. Record answers in "item response" column. If missing, mark with an X 
    
2. Perform reversals as indicated, and sum individual items to obtain a score. 
3. Multiply the sum of the item scores by the number of items in the subscale, then 
divide by the number of items answered. This produces the subscale score. 
4. Add subscale scores to derive total scores (TOI, FACT-G & FAACT).  
5. The higher the score, the better the QOL. 
 
 
Subscale 
 
  Item Code    Reverse item?       Item response         Item Score  
 
PHYSICAL 
GP1 
 
4 
- 
________ 
 
=________ 
WELL-BEING 
GP2 
 
4 
- 
________ 
 
=________ 
   (PWB) 
GP3 
 
4 
- 
________ 
 
=________ 
       
GP4 
 
4 
- 
________ 
 
=________ 
       
GP5 
 
4 
- 
________ 
 
=________ 
       
GP6 
 
4 
- 
________ 
 
=________ 
       
GP7 
 
4 
- 
________ 
 
=________ 
 
Sum individual item scores: ________   
Multiply by 7: ________ 
Divide by number of items answered: ________=PWB subscale score 
 
 
SOCIAL/FAMILY 
GS1 
 
0 
+ 
________ 
 
=________ 
WELL-BEING 
GS2 
 
0 
+ 
________ 
 
=________ 
    (SWB) 
GS3 
 
0 
+ 
________ 
 
=________ 
       
GS4 
 
0 
+ 
________ 
 
=________ 
       
GS5 
 
0 
+ 
________ 
 
=________ 
    
GS6 
 
0 
+ 
________ 
 
=________ 
       
GS7 
 
0 
+ 
________ 
 
=________ 
 
Sum individual item scores: ________   
Multiply by 7: ________ 
Divide by number of items answered: ________=SWB subscale score 
 
 
EMOTIONAL 
GE1 
4 
- 
________ 
 
=________ 
WELL-BEING 
GE2 
0 
+ 
________ 
 
=________ 
Score range: 0-28 
Score range: 0-28 


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    (EWB) 
GE3 
4 
- 
________ 
 
=________ 
       
GE4 
4 
- 
________ 
 
=________ 
      
GE5 
4 
- 
________ 
 
=________ 
 
 
 
GE6 
4 
- 
________ 
 
=________ 
 
Sum individual item scores: ________   
Multiply by 6: ________ 
Divide by number of items answered: ________=EWB subscale score 
 
 
FUNCTIONAL   
GF1 
 
0 
+ 
________ 
 
=________ 
WELL-BEING  
GF2 
 
0 
+ 
________ 
 
=________ 
     (FWB) 
GF3 
 
0 
+ 
________ 
 
=________ 
       
GF4 
 
0 
+ 
________ 
 
=________ 
       
GF5 
 
0 
+ 
________ 
 
=________ 
       
GF6 
 
0 
+ 
________ 
 
=________ 
       
GF7 
 
0 
+ 
________ 
 
=________ 
 
Sum individual item scores: ________   
Multiply by 7: ________ 
Divide by number of items answered: ________=FWB subscale score 
 
 
FAACT Scoring Guidelines (Version 4) – Page 2 
 
Subscale 
         Item Code       Reverse item?            Item response          Item Score  
 
ANOREXIA 
 
C6 
 
0 
+ 
________ 
 
=________ 
CACHEXIA 
 
ACT1  
0 
+ 
________ 
 
=________ 
SUBSCALE 
 
ACT2  
4 
- 
________ 
 
=________ 
   (ACS) 
 
ACT3  
4 
- 
________ 
 
=________ 
      
ACT4  
4 
- 
________ 
 
=________ 
       
ACT6  
4 
- 
________ 
 
=________ 
       
ACT7  
4 
- 
________ 
 
=________ 
       
ACT9  
4 
- 
________ 
 
=________ 
       
O2 
 
4 
- 
________ 
 
=________ 
       
ACT10  
4 
- 
________ 
 
=________ 
       
ACT11  
4 
- 
________ 
 
=________ 
       
ACT13  
0 
+ 
________ 
 
=________ 
 
Sum individual item scores:________   
Multiply by 12: ________ 
Divide by number of items answered: ________=AC subscale score 
 
 
To derive a FAACT Trial Outcome Index (TOI): 
 
 
__________ + __________ + __________ =________=FAACT 
TOI 
(PWB score)   (FWB score)   (ACS score)   
 
 
To Derive a FACT-G total score: 
Score range: 0-24 
Score range: 0-28 
Score range: 0-104 
Score range: 0-108 
Score range: 0-48 


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        __________ + __________ + __________ + __________=________=FACT-
G Total score 
        (PWB score)    (SWB score)   (EWB score)  (FWB score) 
 
 
 
To Derive a FAACT total score: 
 
 
              _________ + __________ + __________ + __________ + __________ 
=________=FAACT Total score 
                            (PWB score)  (SWB score)   (EWB score)  (FWB score)   (ACS score) 
 
 
*For guidelines on handling missing data and scoring options, please refer to the Administration and 
Scoring Guidelines in the manual or on-line at www.facit.org. 
 
The following scores are also derived from the FAACT measure: 
• 
5-item Anorexia Symptom Subscale (5-IASS): obtained by summing the 5 
anorexia symptom reversed items scores within the ACS subscale (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 Scale: obtained by summing the 4 anorexia concern 
reversed items scores within the ACS subscale (i.e., “amount I eat sufficient”, “worried 
about weight”, “concerned about thinness”, and “pressured to eat”); the range of 
possible scores is 0-16. 
The following scores will be computed: 
- 
5-IASS = C6+(4-ACT3)+(4-ACT6)+(4-ACT7)+(4-ACT10)  
- 
4-item Anorexia Concerns Subscale = ACT1+(4-ACT2)+(4-ACT4)+(4-ACT9) 
 
FACIT-Fatigue Subscale Scoring Guidelines (Version 4) – Page 1 
 
Instructions: * 
1. Record answers in "item response" column. If missing, mark with an X 
    
2. Perform reversals as indicated and sum individual items to obtain a score. 
3. Multiply the sum of the item scores by the number of items in the subscale, then 
divide by the number of items answered.  This produces the subscale score. 
4. The higher the score, the better the QOL. 
 
 
Subscale 
         Item Code       Reverse item?            Item response          Item Score  
 
FATIGUE 
 
HI7 
      
4 
- 
________ 
 
=________ 
SUBSCALE 
 
HI12 
 
4 
- 
________ 
 
=________ 
    
 
 
An1 
 
4 
- 
________ 
 
=________ 
An2 
 
4 
- 
________ 
 
=________ 
An3 
 
4 
- 
________ 
 
=________ 
Score range: 0-156 
Score range: 0-52 


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An4 
 
4 
- 
________ 
 
=________ 
An5 
 
0 
+ 
________ 
 
=________ 
An7 
 
0 
+ 
________ 
 
=________ 
An8 
 
4 
- 
________ 
 
=________ 
An12 
 
4 
- 
________ 
 
=________ 
An14 
 
4 
- 
________ 
 
=________ 
An15 
 
4 
- 
________ 
 
=________ 
An16 
 
4 
- 
________ 
 
=________ 
 
Sum individual item scores: ________   
Multiply by 13: ________ 
Divide by number of items answered: ________=Fatigue Subscale score 
 
 
Additionally, based on the here-above Fatigue Subscale (FACIT-F), the Physical wellbeing 
and the Functional well-being, the FACIT-F TOI will be computed as: FACIT-F TOI = 
FACIT-F + PWB + FWB; the range of possible scores is 0-108. 
 
12.4. 
Validation and QC Plan 
 
The program reviewer is responsible for reviewing each project program and output 
associated with deliverable product. Program logs will be reviewed for logical, syntax 
and fatal errors. The review in SAS will include, but is not limited to, all ERRORS, 
WARNINGS, BY-VALUE merge messages, NOTES, and UNINITIALIZED variables. 
Program logs will also be reviewed for accurate and consistent variable and 
observation counts following each procedure and data step. 
A quality control (QC) statistician will be responsible for checking and reviewing the 
work produced using whatever method he/she feels is appropriate (e.g., SAS code 
review, hand calculation, etc.) to confirm the quality of the output. 
Outputs will be reviewed for typographical errors, misspellings and spurious values or 
results and to check the consistency with the SAP. Outputs will be cross-checked 
against each other for accuracy and consistency. This procedure will include 
comparisons of subject group numbers, counts of subjects at each observation point, 
and consistency of results for variables between outputs. 
Findings of the QC reviews will be communicated to the party responsible for making 
necessary changes. The programs will be QC reviewed again after modifications. 
After final review, when no further changes are required to produce the deliverable, the 
program reviewer and QC statistician will produce documentation to indicate that they 
have successfully performed all of their responsibilities. 
 
12.5. 
Mock Tables 
The mock TLFs are included into a separate document and have been reviewed and 
agreed along with the SAP text. 
 


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13. 
CHANGES IN THE PLANNED ANALYSIS FROM STUDY 
PROTOCOL 
The following changes from study protocol have been considered: 
Efficacy Analysis 
• Sensitivity Analysis:  
o a subset of patients performed visits remotely due to COVID-19 
restrictions and some important assessment (Body Weight) was 
collected and reported by the patients during the phone call. A sensitivity 
analysis not foreseen in the study protocol has been added in the SAP, 
by setting at missing the impacted values and managing these missing 
values using the Multiple Imputation process. 
o as the presence of fluid retention may affect the assessment of weight, 
an additional sensitivity analyses (other than the one already anticipated 
in the protocol) will be conducted for the primary endpoint "Mean change 
in body weight from baseline over 12 weeks, excluding entirely patients 
with fluid retention observed at any point during the study. 
o some cases of mis-stratifications were confirmed for a subset of patients. 
Thus, a sensitivity analysis has been added in the SAP to repeat the 
primary efficacy analysis using the correct strata information as part of 
the covariates included in the statistical model. 
• Exploratory Analysis:  
o with the aim to better describe the clinical benefit and the responsiveness 
to anamorelin, a separate analysis (Changes from baseline to Week 3, 
6, 9, 12, 15, 18, 21, and 24) on the most important patient-reported 
symptoms and functional items extracted from FAACT total score have 
been added: 
▪ Items GP1, GP7, GF5, GF6 GF7 related to physical and functional 
well-being  
▪ Items ACT1, ACT2, ACT4, ACT13 related to A/CS part 
▪ Items HI7, HI12, AN2, AN5, AN12 related to FACIT-F (Fatigue) 
questionnaire 
o the evaluation of the effect of anamorelin on Overall Survival has been 
incorporated into the Study Design as a safety objective to verify that no 
detrimental effect of anamorelin were observed. Anamorelin is not an 
anticancer medication, and as such, it is not expected to have a 
measurable positive impact on PFS or OS. The ANAM studies were not 
designed to detect a potential survival benefit of anamorelin mediated by 
body weight gain and improvement of anorexia symptoms. The 
relationship between changes in body weight and the 5-IASS will 
therefore not be analyzed, neither in the overall study population nor at 


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the level of treatment arms. Composite Clinical Response (CCR) 
definition was updated using final clinically meaningful thresholds for 
body weight gain (1.5 kg) and 5-IASS increase (3 points) resulted from 
the quantitative analysis of a separate study (7), combined with evidence 
from the embedded qualitative interview sub-study (6) 
o With the aim to present a complete picture of the primary endpoint, the 
absolute change from baseline in body weight to Week 12 will also be 
presented for some pre-defined categories agreed during BDRM. 
• Subgroup Analysis (Section 8.6): due to the inadequate number of patients 
within each subgroup, as described during the BDRM, the subgroups analysis 
(analysis of the coprimary and secondary efficacy endpoints in each stratum 
defined by the variable) will not be performed for the following variables: 
o Race, 
o Ethnicity 
o Country (Geographic region) 
o Patients with at least one treatment emergent adverse event with 
preferred term related to fluid retention and/or patients with signs of 
edema. 
Safety Analysis 
• Laboratory Data: for Hematology and Blood Chemistry descriptive statistics 
based on absolute value and change from baseline by parameter and visits 
have been added. This analysis has been added because by protocol shift 
tables for only a subset of Hematology and Blood Chemistry parameters were 
planned. 
• Overall Survival: an analysis, based on the stratified Cox regression model has 
been planned, in addition to the pre-planned analysis based on Kaplan-Meier 
estimates. 
• 
Tumor assessments: The best overall tumor response summary as planned in 
the protocol has been replaced by the last overall response. This is because 
anamorelin is not expected to have an impact on tumor and the best response 
was finally not considered of safety interest. 
 
 


T AN001 
Effective Date 25 JUL 2022 
Approved Version 2.00 
 
Helsinn BEL-LSP_E0295_ANAM-17-20 SAP v1.0 Final 12MAY20233  
66/66 
CONFIDENTIAL 
 
14. 
REFERENCES 
1. Ratitch B. Multiple Imputations. In: O'Kelly M and Ratitch B, editors. Clinical 
Trial with Missing Data: A Guide for Practitioners. West Sussex: John Wiley & 
Sons Ltd, 2014. p 185-256. 
2. Ratitch B, Lipkovic I, and O'Kelly M. Combining Analysis Results from Multiply 
Imputed Categorical Data. PharmaSUG 2013 - Paper SP03. 2013. 
3. Yang Yuan, SAS Institute Inc. Sensitivity Analysis in Multiple Imputation for 
Missing Data. SAS Proceedings, SAS Global Forum 2014: Paper SAS270-
2014 
4. Clinical Study Report HT-ANAM-301 - ROMANA 1 - Anamorelin HLC in the 
treatment of Non-Small Cell Lung Cancer-Cachexia (NSCLC-C): a 
randomized, double-blind, placebo-controlled, multicenter, Phase 3 study to 
evaluate the safety and efficacy of anamorelin HCL in patients with NSCLC-C. 
5. Clinical Study Report HT-ANAM-302 - ROMANA 2 – Anamorelin HLC in the 
treatment of Non-Small Cell Lung Cancer-Cachexia (NSCLC-C): a 
randomized, double-blind, placebo-controlled, multicenter, Phase 3 study to 
evaluate the safety and efficacy of anamorelin HCL in patients with NSCLC-C. 
6. Qualitative Embedded Interviews among Phase 3 Clinical Trial Patients with 
Advanced Non-small Cell Lung Cancer (NSCLC) and Malignancy-associated 
Weight Loss and Anorexia. EVA-31327-01 | April 28, 2023| Version 3.0. 
7. Responder Definitions for 5-Item Anorexia Symptoms Subscale and Body 
Weight in Patients with Advanced Non-small Cell Lung Cancer and 
Malignancy-associated Weight Loss and Anorexia. Results Memo. EVA-
31327-00-001 | 8 May 2023 | Version 5.0. 
8. COVID-19 Subject Remote Visit Instruction_version 1.0_FINAL_06 April 2020