A Randomized, Double-blind, and Placebo Controlled Multicenter Phase II Trial Evaluating Anamorelin in the Prevention of Cancer Induced-Weight Loss and Anorexia in Patients Receiving First-line Treatment of Advanced Pancreatic Cancer
Phase: PHASE2
Conditions: Metastatic Pancreatic Cancer
Sponsor: Lahey Clinic

A Randomized, Double-blind, and Placebo Controlled Multicenter Phase II 
Trial Evaluating Anamorelin in the Prevention of Cancer Induced-Weight 
Loss and Anorexia in Patients Receiving First-line Treatment of Advanced 
Pancreatic Ductal Cancer
NCT#: 04844970
Protocol#: LCID 20193054
 
IND#: 155817
Principal Investigator: Keith Stuart, MD
Co-Investigators:
Mary Linton B Peters, MD (Beth Israel Deaconess Medical Center)
Angela Alistar, MD (Morristown Medical Center)
Najeeb Al Hallak, MD (Karmanos Cancer Institute)
Kunal C Kadakia, MD (Levine Cancer Institute)
Paige Widick, MD (Beth Israel Deaconess Medical Center)
Andrew Hendifar, MD (Cedar Sinai)
Patrick Loehrer, MD (University of Indiana)
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Protocol Signature Page
Title: A Randomized, Double-blind, and Placebo Controlled Multicenter Phase II Trial 
Evaluating Anamorelin in the Prevention of Cancer Induced-Weight Loss and Anorexia in 
Patients Receiving First-line Treatment of Advanced Pancreatic Ductal Cancer
__________________________________________   
_______________
Signature, Site Principal Investigator
             Date
Printed Name: ______________________________
Institution: _________________________________
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Study Personnel Contact List
Sponsor:
Lahey Hospital & Medical Center
41 Mall Rd.
Burlington, MA 01805
Principal Investigator:
Lahey Hospital & Medical Center
Keith Stuart
Office: (781) 744-8400
Fax: (781) 744-5192
Email:Keith.Stuart@lahey.org
Clinical Research Program Manager:
Lahey Hospital & Medical Center
Office: (781) 744-3421
Fax: (781)744-5192
Statistics: 
Quartesian LLC
Andrei Breazna
Email: Andrei.breazna@quartesian.com
     
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Protocol Synopsis
Study Title
A Randomized, Double-blind, and Placebo Controlled Multicenter 
Phase II Trial Evaluating Anamorelin in the Prevention of Cancer 
Induced-Weight Loss and Anorexia in Patients Receiving First-line 
Treatment of Advanced Pancreatic Ductal Cancer
Sponsor
Lahey Hospital & Medical Center
Countries and sites
Multi-center national study with sites in the US 
Clinical Phase
Phase II
Indication
Treatment of malignancy-associated weight-loss and anorexia in 
patients with pancreatic adenocarcinoma
Study Design
Multicenter, double-blind, randomized, placebo-controlled study to 
evaluate the efficacy and safety of anamorelin HCl. 100 subjects 
with advanced pancreatic ductal adenocarcinoma and weight loss 
will be randomized 1:1 to anamorelin HCl 100 mg or placebo, taken 
orally once daily (QD) for a total of 25 weeks. Subjects 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 at 13 weeks
Secondary: To evaluate the improvement in anorexia symptoms and 
the safety and tolerability of anamorelin HCl at 13 weeks
Treatment groups
Group 1/Test group: Anamorelin HCl 100mg daily (Administered as 
100mg tablets taken in fasting state)
Group 2/Placebo group: Placebo daily (Administered as matching 
placebo tablets taken in fasting state)
Drug administration
Subjects will take 1 tablet on Day 1 (starting 3-5 days before the 
chemotherapy and daily thereafter until visit 10 (Week 25). 
Subjects will be supplied with study drug at visit 0 (Screening), and 
re-supplied at Visit 4 (Week 7), Visit 7 (Week 13). 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.
Study duration
A total of 25 weeks to completion of study
Number of subjects
A total of 100 subjects with PDAC (advanced pancreatic ductal 
adenocarcinoma) will be randomized 1:1 to anamorelin or placebo. 
A total of 50 subjects in each group.
Target study population
Advanced pancreatic ductal adenocarcinoma-adult subjects with 
body mass index < 20 kg/m2  or with involuntary weight loss of >5% 
within 6 months prior to screening 
Inclusion Criteria
1. Signed written informed consent
3. Documented histologic or cytologic diagnosis of American Joint 
Committee on Cancer (AJCC) unresectable or metastatic pancreatic 
adenocarcinoma
4. Body mass index < 20 kg/m2 or with involuntary weight loss
>5% within 6 months prior to screening
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2. Female or male ≥18 years of 

1 and ≤ 37 points on 
the 12-item FAACT A/CS
6. Subjects eligible to receive first line palliative chemotherapy
7. ECOG performance status 0 or 1 at screening 
 
9. Appropriate treatment with pancreatic enzyme replacement prior 
to trial initiation per treating physician’s discretion.
10. Female subjects shall be: 
a) of non-childbearing potential
b) of childbearing potential using reliable contraceptive 
measures and having a negative blood/urine pregnancy test at 
screening.
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 0). 
Exclusion Criteria
1. Patient with other forms of pancreatic cancer (e.g., 
neuroendocrine tumors)
2. Patient undergoing major surgery within 4 weeks of 
randomization or plans to undergo major surgery during study 
period
3. Women who are pregnant or breastfeeding
4. Patient with alternative cause of anorexia as determined by the 
investigator including: a) severe COPD requiring O2, b) severe 
heart failure (NYHA Class III- IV), c) second malignancy
5. Reversible causes of reduced food intake as determined by the 
investigator including but not limited to: severe mucositis (≥ 
NCI CTCAE version 5.0 grade 3), mechanical obstruction, 
severe nausea, vomiting, or diarrhea (≥ NCI CTCAE version 5.0 
grade 3)
6. Patient unable to swallow pills
7. Patient with history of bariatric surgery, gastrectomy, or 
malabsorption disorder (gastritis, esophagitis)
8. Use of strong CYP3A4 inhibitors two weeks prior to study entry 
9. Patient currently taking medications/compounds intended to 
increase appetite or decrease weight loss (e.g. testosterone, 
megestrol acetate, cannabis products, chronic corticosteroids, 
olanzapine for reason other than nausea control, mirtazapine 
(allowed if >4 weeks of use as therapy for depression)
10. Patient currently taking methylphenidate
11. Patient with current use of tube feeding or parenteral feeding
1 The 5-item Anorexia Symptom Scale includes item C6, ACT3, ACT6, ACT7 and ACT10 in appendix 2.
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8. Acceptable hepatic function 
as defined by total bilirubin < 1.
6 mg/dl unless associated with 
Gilbert syndrome, then total 
points on the 5-item 
Anorexia Symptom
5. Ongoing problems with appetite/eating associated 
with the underlying cancer as determined by having

12.
2.
13. 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
14. Patient with hyperglycemia that is not under management
15. Patient with uncontrolled pain.
16. 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
17. Enrollment in a previous study with anamorelin HCl
18. Enrollment in another clinical trial during the time of this trial.
All exclusion criteria will be checked at screening visit (Visit 0). 
Efficacy Assessment
Primary Efficacy Endpoints:
Change in body weight from baseline to week 13
Secondary Endpoints:
1. Absolute change in the FAACT 5 item Anorexia Symptom 
Score from baseline to week 13 as measured every 2 weeks
2. Safety and tolerability
3. Overall survival
4. Radiologic response to chemotherapy using CT/MRI by 
RECIST 1.1 criteria assessed at week 13 
5. Weight gain at week 25
6. Change in FACIT-F: fatigue subscale, at baseline, week 13 
and week 25
Exploratory Endpoints
1. Number of unplanned visits for symptom management as 
defined by unscheduled clinic visits, Emergency Room 
visits, or hospitalizations.
2. Percent of patients who require a change in either dose or 
treatment interval of intended chemotherapy. 
2 Grading system of International Ascites Club: grade 1: mild, detectable only by ultrasound; grade 2: moderate, 
moderate symmetrical distension of abdomen; grade 3: large or gross ascites, abdominal distention. (Reference: 
Hepatology 2003 Jul; 38 (1): 258
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Patient with pleural effusion requiring thoracentesis, 
pericardial effusion requiring drainage 2+ edema or

3. Body Composition Analysis:

Evaluate if baseline body composition measures predict 
tumor response or biochemical response (cancer antigen 19-9 
(CA 19-9)).

Evaluate if baseline body composition measures predict 
chemotherapy toxicities.  

Analyze if change in body composition is influenced by 
baseline demographic and disease-related characteristics.
Safety Assessment
The following safety assessments will be obtained during the Study: 
physical examination (PE), vital signs, 12-lead 
electrocardiogram (ECG), CBC and Differential/CBC and 
ANC, comprehensive metabolic profile, tumor marker 
(CA19-9), urinalysis, adverse events (AEs) assessment, the 
overall survival on all subjects 
Stratification
Treatment Regimens – FOLFIRNOX or Gemcitabine/Abraxane and 
±10% weight loss prior to enrollment 
Statistical Analysis of 
Efficacy
Analysis Sets
Statistical analyses will be performed on the following subjects’ 
sets:
●The Full Analysis Set (FAS): all randomized subjects 
●The Modified Intent-to-Treat (MITT) includes all 
randomized subjects who take at least one dose of trial 
medication and for which post randomization data are 
collected. 
●Per-Protocol (PP): subset of the randomized subjects who do 
not have major protocol violations
●Safety: all subjects who receive any study drug and will be 
summarized as per actual treatment
Primary Efficacy Endpoint Hypotheses and Tests
All summaries except safety and discontinuation of study treatment 
will be performed according to the Intent-to-Treat paradigm (as 
randomized)-unless otherwise requested
The null hypothesis H0 and the alternative H1 are set up as:
H0: no treatment effect
H1: the primary endpoint has different means.
Sensitivity Analyses
Sensitivity analyses may be performed; some will be detailed and 
pre-specified in the Statistical Analysis Plan (SAP)
Supportive Analyses
Two analyses similar to the primary efficacy analysis will be 
conducted; one on the FAS population and another one on the PP. 
Primary efficacy endpoint will be presented for all the subgroups by 
the mean of a Forest Plot.
Secondary Efficacy Endpoints Hypotheses and Tests
If the primary endpoint shows benefit at the two-sided significance 
level of 5%, the secondary endpoints will be evaluated for providing 
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significant benefit following a hierarchal approach, using change in 
anorexia score at Week 13 as the first secondary endpoint, the 
change in radiologic response per RECIST 1.1 criteria at Week 
 
as the second secondary endpoint, change in patient in FACIT-F 
total score at Week 
as the third secondary endpoint, and overall 
survival at week 25 as the final secondary endpoint.
Exploratory Efficacy Analysis
The exploratory efficacy analyses are aimed to explore the effect of 
the anamorelin on different endpoints and/or time points.
All the quantitative exploratory endpoints analyses will use the same 
model described above for the secondary endpoints. Binary 
endpoints (responder analyses) will be analyzed using a CMH model 
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. Specific to the exploratory efficacy analyses as they relate to 
body composition, primary analysis of this exploratory aim will 
evaluate weight change from baseline to 13 weeks as a function of 
baseline body composition measures.  Initially, all subjects will be 
pooled together to assess the statistical significance of baseline body 
composition measures (BBCMs) on weight change. Univariate 
linear models (regression or Analysis of Variance) will be used to 
identify individual prognostic factors among the BBCMs.  Body 
composition measures identified to be individually significant 
prognostic factors (p < 0.05) will be included in a multivariable 
model.  Backwards elimination (p < 0.05) will be utilized to identify 
BBCMs that are independently prognostic for weight change.  
Treatment group will then be added to a model including these 
independently prognostic BBCMs to assess the treatment group 
effect modification associated with these body composition 
measures. A similar modelling strategy will be used to assess the 
impact BBCMs on tumor response, biochemical response, and 
maximum severity great toxicities; however, logistic regression will 
be used to analyze these endpoints. Changes in BBCMs from 
baseline to Week 13 will be analyzed separately to assess the impact 
of demographic and disease-related characteristics on these changed 
in BBCMs. Body composition measures assessed by thresholds 
(Section H-10) will be analyzed using ordered-categorical logistic 
regression models and body composition measures assess 
quantitatively will be analyzed using linear models.
Statistical Analysis of 
Safety
All safety and tolerability data will be summarized descriptively 
according to the “As Treated” paradigm.
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CONTENTS
A. ABSTRACT............................................................................................................................11
B. SPECIFIC AIMS.....................................................................................................................11
1.0
Study Objectives.............................................................................................................11
2.0
Study Endpoint...............................................................................................................11
3.0
Safety assessments..........................................................................................................11
C. BACKGROUND AND SIGNIFICANCE...............................................................................11
1.0
Background.....................................................................................................................12
2.0
Anamorelin: preclinical and clinical data.......................................................................13
3.0
Anamorelin: Phase 1 Clinical Data.................................................................................13
4.0
Anamorelin: Phase II/III Clinical Data...........................................................................14
D. STUDY RATIONALE............................................................................................................14
1.0
Rationale for Study Population.......................................................................................14
2.0
Rationale for Study Design.............................................................................................15
3.0
Rationale for Selected Study Duration...........................................................................15
4.0 Rational for Selected Dose Range.....................................................................................15
E. STUDY PLAN.........................................................................................................................15
1.0
Study Design...................................................................................................................16
2.0
Study Duration................................................................................................................16
3.0
Study population.............................................................................................................16
4.0
Eligibility........................................................................................................................16
F. STUDY DRUG MANAGEMENT..........................................................................................18
1.0
Description of study treatments......................................................................................18
2.0
Treatment Groups...........................................................................................................18
3.0
Dose and Administration................................................................................................18
4.0
Packaging........................................................................................................................18
5.0
Storage............................................................................................................................18
6.0
Study Drug Distribution.................................................................................................18
7.0
Accountability.................................................................................................................19
8.0
Randomization and Administration of Study Treatment................................................19
9.0
Blinding/Unblinding.......................................................................................................19
10.0 Management of treatment overdosage............................................................................19
11.0 Occupational safety........................................................................................................19
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12.0 Prior and concomitant medications................................................................................20
13.0 Rescue medications........................................................................................................21
14.0 Treatment compliance....................................................................................................21
G. STUDY SCHEDULE OF ASSESSMENTS...........................................................................22
H. METHODS OF ASSESSMENT.............................................................................................24
1.0
Adverse Events...............................................................................................................24
2.0
Classification of Adverse Events....................................................................................25
3.0
Severity...........................................................................................................................25
4.0
Relationship to Investigational Study Drug....................................................................26
5.0
Reporting Adverse Events..............................................................................................27
6.0
Reporting Serious Adverse Events.................................................................................27
7.0
Follow-up of Serious Adverse Events............................................................................28
8.0
Safety Monitoring Plan...................................................................................................28
9.0
Pregnancy Report............................................................................................................28
10.0 Patient Discontinuation...................................................................................................28
I.
STATISTICS...........................................................................................................................29
J.
ETHICAL AND REGULATORY ASPECTS........................................................................30
1.0
Ethical Considerations....................................................................................................30
2.0
Laws and Regulations.....................................................................................................30
3.0
Patient’s information sheet and informed consent form.................................................30
4.0
Protocol amendments......................................................................................................30
5.0
Protocol deviations.........................................................................................................31
6.0
Project Management and Data Collection......................................................................31
7.0
Study Monitoring and Quality Assurance......................................................................32
8.0
Study Documentation and Records retention.................................................................32
9.0
Confidentiality................................................................................................................33
K. REFERENCES........................................................................................................................34
APPENDIX 1: PROHIBITED MEDICATIONS..........................................................................36
APPENDIX 2: FAACT- FUNCTIONAL ASSESSMENT OF ANOREXIA/CACHEXIA 
TREATMENT QUESTIONNAIRE........................................................................................37
APPENDIX 3: FACIT- FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY-
FATIGUE SUBSCALE...........................................................................................................40
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A. ABSTRACT
A Randomized, Double-blind, and Placebo Controlled Multicenter Phase II Trial Evaluating 
Anamorelin in the Prevention of Cancer Induced-Weight Loss and Anorexia in Patients 
Receiving First-line Treatment of Advanced Pancreatic Cancer
B. SPECIFIC AIMS
1.0 Study Objectives
1. Primary Objective: To demonstrate anamorelin HCl superiority over placebo on gain in 
body weight.
2. Secondary Objectives: To evaluate improvement in anorexia, the safety and tolerability 
of Anamorelin HCl in subjects with pancreatic cancer.
2.0 Study Endpoint
●Primary efficacy endpoint
The primary efficacy endpoint for this study is change of body weight from baseline to 
week 13 
●Secondary efficacy endpoints
Secondary efficacy endpoints will supplement our primary endpoints by further 
elucidating the degree and manner in which Anamorelin HCl improves outcomes. These 
will include:
▪
Absolute change in the FAACT 5 item Anorexia Symptom Score from baseline 
score at week 13. 
▪
Safety and tolerability
▪
Overall survival
▪
Radiologic response to chemotherapy using CT/MRI by RECIST 1.1 criteria 
assessed at week 13
▪
Weight gain at 25 weeks
▪
Change in FACIT-F: fatigue subscale, at baseline, week 13 and week 25
●Exploratory endpoints
▪
Number of unplanned visits for symptom management as defined by unscheduled 
clinic visits, Emergency Room visits, or hospitalizations.
▪
Percent of patients who require a change in either  dose or treatment interval of 
intended chemotherapy
3.0 Safety assessments
The following safety assessments will be performed: physical examination (PE), vital signs, 12-
lead electrocardiogram (ECG), CBC and Differential/CBC and ANC, comprehensive profile, 
tumor marker (CA 19-9), and urinalysis, adverse events (AEs) assessment, and the overall 
survival on all subjects. Please refer to section G Study Schedule of Assessments for 
timing/detail of assessments.
C. BACKGROUND AND SIGNIFICANCE
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1.0 Background
Pancreatic cancer is the fifth leading cause of cancer deaths in the United States with rising 
numbers each year (1). Due to its aggressive nature, patients with pancreatic ductal 
adenocarcinoma (the most common subtype of pancreatic cancer) often present with advanced, 
non-resectable disease. Prognosis in these cases is poor with life expectancy 6-15 months with 
the use of standard of care therapy (2, 3). Weight loss and cachexia are commonly seen in PDAC 
with 90% of patients at risk of developing it during the course of their diagnosis and treatment 
(4). Weight loss, wasting, and cachexia have been shown to have a deleterious effect on response 
to treatment and confer a poor prognosis (5). 
There remains a dearth of therapeutics available to combat the development of cachexia in 
patients with pancreatic adenocarcinoma. The current study aims to provide an option in the 
management of cancer-cachexia in an effort to improve prognosis and response to therapy in 
patients with pancreatic cancer.
The definition of cancer cachexia has changed significantly over time. Prior to consensus 
evaluation, definitions focused primarily on patient performance status and weight loss. Per 
current ASCO cancer cachexia guidelines-Journal of Clinical Oncology, cachexia is defined as 
the following:
-
Weight loss >5% in preceding 6 months 
-
BMI <20 kg/m2 and >2% weight loss
-
Loss of  muscle mass and >2% weight loss  
Reduced food intake due to anorexia is a hallmark in the development of cachexia. While the 
etiology of underlying decreased intake is not well understood, there are some contributing 
factors that have been clearly demonstrated in previous studies. First, uncontrolled cancer 
symptoms including pain, change in taste, and nausea certainly contribute to decreased intake.  
Metabolic changes, particularly via elevated levels of inflammation in the setting of malignancy 
contribute to increased catabolism in patients with active cancer (6). Finally, physiologically, the 
homeostatic control of metabolism is modified due to alterations in the manner in which the 
hypothalamus controls appetite and food intake (7). 
As previously noted, the presence of cachexia is an independent prognostic factor in patients 
with pancreatic cancer. Per the IMPACT study (8), the development of sarcopenia/muscle 
wasting during the course of treatment was a poor prognostic indicator irrespective of weight 
loss/gain. An additional study by Choi et al (9) demonstrated that sarcopenia was an independent 
predictor of negative outcome even in patients with early stage disease undergoing surgical 
intervention. Sarcopenia is a single aspect of cancer cachexia; anorexia alone also contributes to 
decreased quality of life as well as changes to treatment plans. Some patients’ weight loss can be 
so severe that it results in treatment delays, dose reductions, or even treatment cessation which 
prevents these patients from achieving maximum benefit of their treatment plans (10). These 
findings have prompted a call to investigate strategies that will focus on aspects of cachexia 
separate from sarcopenia, including anorexia and weight loss that may impact patient outcomes 
(11). 
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Despite its prevalence and impact on quality of life and patient outcomes, there remains a dearth 
of options to address cancer cachexia. Prior groups have evaluated lifestyle and nutritional 
modifications with some success though compliance was difficult to achieve (12). There remains 
a lack of effective pharmacological interventions for the management of these highly morbid 
cancer sequelae.
Anamorelin HCl is an orally active selective ghrelin agonist that may serve to improve weight 
loss and anorexia via pharmacologic means. Ghrelin, a growth hormone secretagogue receptor, 
has been assessed as a potential target for the treatment of cachexia due to its ability to modulate 
systemic metabolism, regulate food intake, modify glucose metabolism, and protect against 
muscle atrophy (13). Initially it was unclear whether it would make a good target as its half-life 
is very short (approximately 15 minutes); however research on ghrelin and longer active ghrelin 
mimetics has been able to definitively demonstrate its ability to stimulate appetite, increase 
weight gain, and improve gi kinetics (14). 
Anamorelin HCl has demonstrated high affinity for the ghrelin receptor with robust release of 
GH (growth hormone) in in vitro studies. In vivo animal studies with dog and rat subjects were 
able to increased appetite and weight in those subjects (15). A phase 3 study of patients with lung 
cancer demonstrated that the use of Anamorelin HCl resulted in increased lean body mass 
despite no increase in handgrip strength, highlighting its potential usefulness in the treatment of 
cancer related anorexia and weight loss (16). 
2.0 Anamorelin: preclinical and clinical 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, metabolism and excretion of 
anamorelin in rats and mice. Toxicology studies were carried out primarily 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. The most significant toxicity 
discovered during this phase of development of anamorelin HCl was the dose dependent 
prolongation of the cardiac QRS duration and PR interval caused by blockade of cardiac sodium 
ion channels. 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.
3.0 Anamorelin: Phase 1 Clinical Data
Anamorelin HCl has been studied in 15 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. As noted above, Anamorelin HCl was found to increase levels of GH and caused 
significant appetite stimulation, body weight gain, and overall increased food intake. The 
threshold dose required 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 (17). No dose-limiting toxicity was 
observed up to 150 mg with multiple dosing; a single dose of 400 mg was determined to be the 
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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, 
dizziness, and nausea (18). Non-clinical events that were evaluated included transaminases, 
which was infrequent and QTc prolongation. While EKG abnormalities were initially of great 
concern, a dedicated study (HT- ANAM-113) revealed that anamorelin had no significant effect 
on cardiac electrical patterns.  
4.0 Anamorelin: Phase II/III Clinical Data
The phase II program evaluating Anamorelin HCl evaluated its effect on individuals with 
numerous malignancies. 82 subjects were enrolled and randomized to anamorelin 50mg daily or 
placebo. Over 12 weeks, those in the anamorelin group showed significantly greater weight gain 
and increased lean body mass in comparison to the placebo group. Most noteworthy side effects 
included fatigue, dyspnea, and atrial fibrillation (19). 
A second Phase II study evaluated the effect of differing doses of Anamorelin in subjects with 
advanced non-small cell lung cancer (20). 181 subjects were randomized to placebo, 50mg daily 
anamorelin, or 100mg daily anamorelin. There was a clear dose-dependent effect with those in 
the 100mg group on weight gain, performance status, and quality of life metrics.
A phase III program resulted in 2 separate studies, ROMANA-1 and ROMANA-2 both focused 
on subjects with advanced NSCLC. 484 subjects were enrolled at 93 separate sites. All were 
randomized 2:1 to anamorelin 100mg daily or placebo. Neither study resulted in a significant 
improvement in strength over the 12 weeks of study time. However, both studies demonstrated 
statistically significant improvement in lean body mass in the Anamorelin groups. 
The primary purpose of the current study is to evaluate the effect of anamorelin on weight gain 
and anorexia symptoms in subjects with pancreatic ductal adenocarcinoma. 
D. STUDY RATIONALE
1.0 Rationale for Study Population
This study will be performed in adult subjects with advanced pancreatic adenocarcinoma. This 
population was selected for investigation due to the prevalence of anorexia and weight loss 
present at the time of diagnosis. Additionally, baseline weight loss and anorexia over time carry 
prognostic implications including increased symptom burden and shortened survival. 
To adequately assess our desired population, we plan to enroll those with BMI <20 and/or a 5% 
loss in body weight over the preceding 6 months, meeting the consensus criteria for cancer 
related weight loss and anorexia. These subjects are at higher risk for anorexia-related sequelae 
and would be the first group to benefit from an effective therapy. Additionally, as we are also 
assessing improvement in anorexia symptoms over time, our enrolled subjects must also 
demonstrate ongoing concerns with appetite and eating habits. 
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2.0 Rationale for Study Design 
Anorexia and weight loss are common clinical sequelae of uncontrolled, metastatic cancer. These 
effects can impair physical function, reduce quality of life, impair tolerability of anticancer 
therapy, and reduce survival. Anorexia and weight loss are especially challenging problems in 
patients diagnosed with metastatic pancreatic cancer. With an annual incidence approaching 
50,000 patients in the U. S. along, pancreatic cancer has an annual mortality of approximately 
40,000 patients with most individuals succumbing to their disease within two years. Between 70-
8-% of patients with metastatic pancreatic cancer experience cancer related anorexia and weight 
loss, which has been associated with reduced survival, increase risk of disease progression and 
impaired chemotherapy tolerance.  
The study is a randomized, placebo controlled multicenter, Phase II trial to evaluate the efficacy 
and safety of anamorelin HCl. Approximately 100 patients with be enrolled in a 1:1 
randomization to anamorelin HCl 100mg per day given concurrently with first-line 
chemotherapy compared to chemotherapy alone. Patients randomized to anamorelin HCl will 
take it daily for about 25 weeks starting 3-5 days prior to chemotherapy. Both body weight and 
appetite will be measured at enrollment as well as at the initiation of chemotherapy. Patients will 
be stratified by degree of weight loss in the six months prior to enrollment and choice of first-
line chemotherapy.
3.0 Rationale for Selected Study Duration 
The goal of the study was primarily to assess weight gain while on Anamorelin HCl in patients 
undergoing initial palliative treatment for pancreatic cancer. As such, the time frames for the 
study endpoints were aligned with the assessments for radiologic response to therapy 
implemented by the clinicians. Patients begin treatment with Anamorelin HCl 1 week before 
chemotherapy starts. Primary endpoint (weight change) along with a radiologic assessment of the 
primary cancer treatment will be assessed after 12 weeks of chemotherapy. As a means of 
assessing whether the effect of Anamorelin HCl was durable, its effectiveness in patients who 
continued on the study will be reassessed for an additional 12 weeks. Hence, a total of 25 weeks 
of assessment was defined for the study.
4.0 Rational 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 (ROMANA-1 and ROMANA-2) in NSCLC 
subjects 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 
subjects with NSCLC was also observed. Follow up safety evaluation did not demonstrate 
increased adverse events with this dose. Thus, we feel that it provides the highest level of 
efficacy without increased risk of harmful side effects. As there is not a current safe and effective 
treatment for weight loss and anorexia in cancer patients, placebo treatment will be used in the 
control group in this study.
E. STUDY PLAN
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 15

1.0 Study Design
This is a multi-center, double-blind, placebo-controlled trial comparing Anamorelin HCl to 
placebo in subjects with advanced pancreatic adenocarcinoma with outcomes including safety 
and efficacy. 100 subjects will be randomized 1:1 to Anamorelin HCl 100mg daily or placebo for 
a total of 25 weeks.
The randomization will be stratified by the chemotherapy and ± 10%weight loss. Subjects will 
visit the site for evaluation every 2 weeks from week 1 to week 13 then every month from week 
13 to week 25. 
2.0 Study Duration
Each patient will remain on study for 25 weeks. Total number of visits will be 11. Subjects will 
be defined as completing the study when they have completed Visit 10 at week 25. The study 
will conclude when the final patient has completed his/her final visit. 
3.0 Study population
Number of Subjects: A total of 100 subjects will be randomized 1:1 to Anamorelin HCl 100 mg 
or placebo. There will be 50 subjects in each group.
4.0 Eligibility
4.1 Inclusion Criteria:
●Signed written informed consent
●
●Documented histologic or cytologic diagnosis of American Joint Committee on Cancer 
(AJCC) unresectable or metastatic pancreatic adenocarcinoma
●Body mass index < 20 kg/m2 or with involuntary weight loss >5% within 6 months prior 
to screening
●
3 and ≤ 
37 points on the 12-item FAACT A/CS
●Subjects eligible to receive first line palliative chemotherapy
●ECOG performance status 0 or 1 at screening 
●Acceptable hepatic function as defined by total bilirubin < 1.6 mg/dl unless associated 
with Gilbert syndrome, then total bilirubin <2 x ULN, AST (SGOT) and ALT (SGPT) ≤ 
2.5 x ULN or if hepatic metastases are present ≤5 x ULN 
●Appropriate treatment with pancreatic enzyme replacement prior to trial initiation if 
indicated per treating physician’s discretion
●Female subjects shall be: 
●of non-childbearing potential or
●of childbearing potential using reliable contraceptive measures and having a negative 
blood/urine pregnancy test at screening
●The patient must be willing and able to comply with the protocol tests and procedures
4.2 Exclusion Criteria
3 The 5-item Anorexia Symptom Scale includes item C6, ACT3, ACT6, ACT7 and ACT10 in appendix 2.
Version 4.1: September 18, 2023
 16
Ongoing problems with 
appetite/eating associated with the 
underlying cancer, as determined by
Female or male ≥18 years of 

●Patient with other forms of pancreatic cancer (e.g. neuroendocrine tumors)
●Patient undergoing major surgery within 4 weeks of randomization or plans to undergo 
major surgery during study period.
●Women who are pregnant or breastfeeding
●Patient with alternative cause of anorexia as determined by the investigator including: a) 
severe COPD requiring O2, b) severe heart failure (NYHA Class III- IV), c) second 
malignancy
●Reversible causes of reduced food intake as determined by the investigator including but 
not limited to: severe mucositis (≥ NCI CTCAE version 5.0 grade 3), mechanical 
obstruction, severe nausea, vomiting, or diarrhea (≥ NCI CTCAE version 5.0 grade 3)
●Patient unable to swallow pills
●Patient with history of bariatric surgery, gastrectomy, or malabsorption disorder (gastritis, 
esophagitis)
●Use of strong CYP3A4 inhibitors two weeks prior to study entry 
●Patient currently taking medications/compounds intended to increase appetite or decrease 
weight loss (e.g. testosterone, megestrol acetate, cannabis products, methylphenidate, 
chronic corticosteroids, olanzapine for reason other than nausea control, mirtazapine 
(allowed if >4 weeks of use as therapy for depression)
●Patient currently taking methylphenidate
●Patient with current use of tube feeding or parenteral feeding
●
4.
●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
●Patient with hyperglycemia that is not under management
●Patient with uncontrolled pain.
●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
●Enrollment in a previous study with anamorelin HCl
●Enrollment or planned enrollment in another clinical trial during the time of this trial.
4 Grading system of International Ascites Club: grade 1: mild, detectable only by ultrasound; grade 2: moderate, 
moderate symmetrical distension of abdomen; grade 3: large or gross ascites, abdominal distention. (Reference: 
Hepatology 2003 Jul; 38 (1): 258
Version 4.1: September 18, 2023
 17
Patient with pleural effusion 
requiring thoracentesis pericardial

All eligibility criteria will be checked at screening visit (Visit 0).
F. STUDY DRUG MANAGEMENT
1.0 Description of study treatments
●Anamorelin HCl, 100mg tablets to be taken daily while fasting at least 1 hour before first 
meal 
●Placebo 
 to be taken daily while fasting at least 1 hour before first meal
2.0 Treatment Groups
●Test group: 100mg Anamorelin HCl daily
●Control group: Placebo
3.0 Dose and Administration
Subjects will take 1 tablet on Day 1 (starting 3-5 days before the chemotherapy and then once 
daily thereafter until visit 10 (Week 25). Subjects will be supplied with study drug at visit 0 
(Screening) and re-supplied at Visit 4 (Week 7) and Visit 7 (Week 13).
Used blister packs will be reviewed at each visit to determine drug compliance. Blister packs will 
be given back to the patient at visits that are not noted as drug resupply visits in section G.
The study drug tablets will be taken orally in mornings while fasting at least 1 hour before 
breakfast. Water is permitted prior to and with study drug.
4.0 Packaging
Packaging will be in the form of blister packs labelled with “Caution: New Drug-Limited by 
Federal Law to Investigational Use”. Study drug will be dispensed at the screening visit (Visit 0) 
and resupplied at visit 4 and visit 7. Patients will be dispensed one extra blister pack at the 
screening visit as an emergency supply in the event a scheduled visit is delayed out of window in 
the Study Scheduled of Assessments. Each pack will be labeled with an individual study drug kit 
number for assistance with identification and subject matching.  
5.0 Storage
An exact inventory of all study drugs must be maintained at the investigational site. The study 
drug must be stored in a locked storage area under controlled environmental 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). Site will 
notify the pharmacy at the Coordinating Center when/if a temperature excursion occurs.
6.0 Study Drug Distribution
The study drug kits will be shipped to participating clinical sites from the Coordinating Center 
Pharmacy.  Study drug shipments to the investigational sites are triggered once the enrolled 
patient is randomized.
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7.0 Accountability
Once the study drug kits are received at the study site, the pharmacist or designated responsible 
person will record receipt of study drug kits in dedicated paper forms. Adequate records of the 
receipt, dispensation and return of study drug kits must be maintained throughout the study.
Used study drug kits will undergo drug accountability performed by the Lahey Coordinating 
Center during the course of the study. Following drug accountability, used study drug kits are to 
be destroyed at the site until the end of the study. Used and unused study drug kits remaining at 
sites at the end of the study will be destroyed to the drug depots for destruction.
8.0 Randomization and Administration of Study Treatment
Randomization will be used to avoid bias in assigning treatments to subjects. 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. A 1:1 randomization with 2 stratification factors: Treatment 
Regimen – FOLFIRINOX or Gemcitabine/Abraxane and ±10% weight loss prior to enrollment 
will be employed. Block sizes, a detailed description of the stratification factors and the 
definitions of the strata, will be pre-specified in a separately crafted randomization plan.
Upon confirmation of subject eligibility (screening visit 0), the investigator at the site will 
request the randomization assignment for the patient from the study Coordinating Center. Each 
randomized patient is assigned a corresponding study drug kit number. The Coordinating Center 
will dispense and ship the assigned study drug kit to Principal Investigator at each participating 
site.
9.0 Blinding/Unblinding
This is a double-blind study. The blinding of the study drugs is guaranteed by the use of identical 
tablets for both placebo and the active drug. 
Unblinding of the patient’s treatment status should be avoided and generally should only be done 
in consultation with the Investigator; it should only be done in the event that unblinding may 
alter treatment decisions or otherwise be medically indicated.
Any unblinding of the study treatment will be performed as per industry standards and local 
practice. 
10.0
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.
11.0
Occupational safety
No testing has been performed on the ability to drive vehicles or operate machinery.
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 19

12.0
Prior and concomitant medications
Concomitant medications will be evaluated and noted from initial visit (day -14 to -7) and 
throughout the trial. If additional hydration or electrolyte replacement is necessary, it will be 
provided and documented in their medical record. 
13.1
Use of corticosteroids
Systemic corticosteroids will be permitted for a maximum of 5 consecutive days for use in 
conjunction with chemotherapy or for sequelae/side effects from treatment. They may not be 
used as “appetite stimulants” at any time while on trial. Subjects requiring inhaled or topical 
corticosteroids may continue these. 
13.2
Prohibited medications
Anamorelin HCl is metabolized via CYP3A4 and CYP2D6. However, Cytochrome P450 
demonstrates moderate inhibitory effects against CYP3A4 and none against CYP2D6. Therefore 
the use of strong CYP3A4 inhibitors will be an exclusion criterion for this study. Drugs that 
strongly inhibit CYP3A4 including various antifungals and antibiotics will need to be avoided 
for the two weeks prior to initiation of the study as well as throughout its duration. If a patient is 
required to take a CYP3A4 inhibitor, then they will have to discontinue the study medication. 
Moderate or weak CYP3A4 inhibitors may be used; however should be avoided if possible. 
Additionally, any use of CYP3A4 inducers should be avoided as they may result in reduction of 
clinical effect. See appendix A for a list of CYP3A4 inhibitors and inducers.
Drugs that may prolong the PR or QRS interval durations are prohibited for the study duration.
Subjects should not take any prescription medication or off-label products intended to increase 
appetite or treat unintentional weight loss during the study; these include: medical marijuana or 
dronabinol, testosterone or testosterone-like agents, olanzapine, megestrol, corticosteroids, or 
mirtazapine (though long term use of olanzapine or mirtazapine for psychiatric needs prior to 
study initiation may continue these therapies). 
Subjects should not be on enteral or parenteral feeding throughout the duration of the clinical 
trial.
13.3
    Concurrent APDC Treatment
All subjects enrolled in this study will be presenting for first line of therapy for metastatic 
disease. Per current NCCN guidelines standard of care therapy for metastatic pancreatic 
adenocarcinoma may include regimens with platinum and non-platinum based chemotherapy 
regimens.
Specific regimens that will be accepted include two regimens; 1. FOLFIRINOX and 2. 
Gemcitabine/Abraxane per investigator preference. Specific dosing and schedules for therapy 
will be at the discretion of the treating physician for each patient. The treating physician will 
calculate the anticipated dose for each patient and record any dose modifications made for 
individual patients while on trial.
Subjects will not be enrolled in any concomitant treatment clinical trials while participating in 
this study.
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 20

13.0
Rescue medications
Not applicable to this study.
14.0
Treatment compliance
Subjects will be instructed to bring all blister packs to each visit during the treatment period for 
assessment of compliance. Compliance will be summarized as proportions of subjects with 
compliance between 80% and 120% of the intended amount of drug
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 21

G. STUDY SCHEDULE OF ASSESSMENTS
Required for 
study
Pre-
trial
Screening 
(visit 0)
Chemo 
teaching 
visit
Week 1 
(visit 1)
Week 3 
(visit 2)
Week 5 
(visit 3)
Week 7 
(visit 4)
Week 9 
(visit 5)
Week 11 
(visit 6)
Week 13 
(visit 7)
Week 17 
(visit 8)
Week 21 
(visit 9)
Week 25 
(visit 10)
Window
 (in days)
Within 14 
days prior to 
randomization
within14 
days of day 
0
Day 012
(± 3)
(± 3)
(± 3)
(± 3)
(± 3)
(± 3)
(± 3)
(± 3)
(± 3)
Informed 
Consent
X
Randomization1
X
Chemotherapy 
Regimen 
selection
X
Medical History
X
Blood/urine 
Pregnancy Test
(if applicable)
X
Concomitant 
Medication
X
X
X
X
X
X
X
X
X
X
X
Physical Exam  
X
X
X
X
X
X
X
X
X
X
X
Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
Vital Signs2
X
X
X
X
X
X
X
X
X
X
X
ECG3
X
X
Urinalysis4
X
Weight
X
X
X
X
X
X
X
X
X
X
X
CBC and 
differential/ANC
X
X
X
X
X
X
X
X
X
X
X
Comprehensive 
Metabolic 
Profile
X
X
X
X
X
X
X
X
X
X
X
Toxicity 
Notation5
X
X
X
X
X
X
X
X
X
X
X
CT or MRI for 
disease 
Assessment6
X
X
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 22

Tumor Marker 
(CA 19-9)
X
X
X
X
FAACT 5 
questionnaire7
X
X
X
X
X
X
X
X
X
X
X
FACIT-F, 
fatigue subscale 
questionnaire8
X
X
X
Chemotherapy 
Initiation 
X
Drug initiation9 
(start drug)
X
Drug resupply13
X
X
Collection of 
unplanned visit 
data10
Collection of 
change of chemo 
schedule or 
chemo dose11
X
X
X
X
X
X
X
X
X
X
Adverse Event 
Collection
X
X
X
X
X
X
X
X
X
X
Overall Survival 
X
X
X
X
X
X
X
X
X
X
1 randomization should happen at least 5 days prior to visit 1 to allow patient start taking the study drug 3-5 days before chemotherapy
2 Vital signs include blood pressure, pulse rate and body temperature, body weight
3 Further ECG assessments depend on treating physician’s discretion
4 Assessing abnormality per treating physician’s discretion
5 Toxicities are defined in section H1.0. Toxicities can be assessed remotely within 24 hours of the study visit if allowed per institutional policy
6 CT or MRI for the screening visit should be within 4 weeks prior to randomization. CT or MRI for disease assessment by RECIST 1.1 criteria
7 See appendix 2 for questionnaire. Questionnaire will be administrated prior to the chemotherapy on day of treatment. Questionnaire can be administrated 
remotely within 24 hours of the study visit if allowed per institutional policy.
8 See appendix 3 for questionnaire. Questionnaire will be administrated prior to the chemotherapy on day of treatment. Questionnaire can be administrated 
remotely within 24 hours of the study visit if allowed per institutional policy.
9 Drug should be initiated 3-5 days prior to the first chemo treatment.
10 Unplanned visits will be collected at any time that event occurs.
11 Change of chemotherapy schedule and/or dose will be collected at any time during treatment.
12 Day 0 is the day that patients start their first chemotherapy treatment.
13 Drug accountability should be documented and recorded  at specified resupply visit (see pharmacy manual for a suggested log).
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H. METHODS OF ASSESSMENT
1.0 Adverse Events
Adverse event recording will begin at the time the informed consent form is signed. Thereafter, 
AEs will be ascertained by direct report from the patient at each visit.
1.1 Definition of Adverse Events
Adverse Event (AE) as defined by the current ICH Guideline for Good Clinical Practice (21) is: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended symptom, clinical change, 
disease development, or lab/imaging finding associated with use of investigational drug or 
device irrespective of whether that finding is related to the drug or device. We would therefore 
consider any such occurrence to be an “AE” at any point after consent was signed whether the 
subject was exposed to the investigational drug or not.
The criterion used for grading the toxicities is the Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5.0.
1.1.1 Expected Toxicities for FOLFIRINOX:
The most common grade 3-4 toxicities are: neutropenia, fatigue, vomiting, diarrhea, 
thrombocytopenia, sensory neuropathy, anemia, elevated alanine aminotransferase (ALT), 
thromboembolism and febrile neutropenia. 
1.1.2 Expected Toxicities for Gemcitabine/Abraxane
Severe hypersensitivity reactions with fatal outcome have been reported with nab-Paclitaxel 
treatment.
1.1.3 AEs Related to Anamorelin HCl Include the Following:

Swelling of lower legs or hands, 

Fatigue, 

Diarrhea

Nausea
Temporary decreases in systolic and diastolic blood pressure have been observed after taking 
first dose of the study drug. 
Study related AEs can be attributed to the following conditions:
●Suspected adverse drug reactions
●Other medical challenges including: injury, accident, exacerbation of an underlying 
medical condition
●abnormal laboratory or physical exam findings
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 24
The following toxicities are relatively common (≥20%) with Abraxane 
and gemcitabine combination treatment: neutropenia, fatigue, peripheral 
neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting,

●Reactions from drug overdose, abuse, withdrawal, hypersensitivity, or toxicity.
Planned interventions or hospitalizations, including surgeries, scheduled prior to the informed 
consent but performed during the study (study procedures, chemotherapy cycles, etc.) should not 
be considered (serious) AEs.
1.2 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
●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.
1.3 Unexpected Adverse Event
An Unexpected Adverse Event is any experience not previously reported (in nature, severity or 
incidence) in the current Investigator’s Brochure for Anamorelin.
1.4 
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.
2.0 Classification of Adverse Events
The Investigator will classify AEs based on their severity and relationship to investigational 
study drug. Every effort must be made by the Investigator to categorize each AE according to its 
severity and its relationship to the investigational product (Anamorelin HCl).
3.0 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 version 5.0) (22) 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;
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 25
   

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.
4.0 Relationship to Investigational Study Drug
For this trial, an AE cause and effect relationship to the study drug will be classified by the 
Investigator and reported as follows.
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 etiologies, 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 etiologies 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 etiologies. 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 etiologies.
Unlikely related
It is more likely that the event is due to other etiologies 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 
Version 4.1: September 18January 31, 2023
 26

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 etiology 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.
Not assessable
The data are insufficient or contradictory to make a meaningful
5.0 Reporting Adverse Events
AE reporting has to be in accordance with the ICH E6 (R2) Guidance on GCP. During the course 
of the study, all AEs, irrespective of the relatedness to the study drugs, must be recorded in detail 
in the source records. 
During the course of an adverse event, severity and/or causality and/or seriousness may change. 
For CRF documentation each adverse event represents one entity from onset to resolution and 
the worst of the observed categories shall be attributed. When an event reoccurs after it has 
resolved, it should be handled as a new AE. However, when the same AE occurs intermittently 
without resolution, it can be recorded as one AE.
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. This includes accidental or intentional use of a drug in an 
amount higher than the dose being studied. An excess dose of study drug does not itself 
constitute an AE, though may contribute to one. All dose modifications (over or under) will be 
recorded and reported to the study Sponsor. If overdose results in AE, this will also be recorded 
and reported. 
6.0  Reporting Serious Adverse Events
All serious adverse events (SAE) (including death and hospitalization) must be reported to Lahey 
Hospital & Medical Center Coordinating Center within one working day of the discovery of the 
event by telephone, email or fax. Applicable SAE forms should be completed in the electronic 
data capture system (EDC) within 5 days of discovery of the event and updated as new 
information becomes available.  All deaths occurring on study must be reported to the Lahey 
Hospital & Medical Center Coordinating Center. These include deaths within 30 days of the end 
of study visits.  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the subject or may 
require intervention. 
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 27

7.0 Follow-up of Serious Adverse Events
SAEs will be followed by the Investigator until the subject is clinically stable, SAE has 
completely resolved, or patient is lost to follow up. This will be particularly important if the SAE 
has not been previously noted, or would have an effect on future monitoring for all sites. An 
updated SAE report should be completed in the EDC, including all missing information from the 
initial report, as appropriate. Any information from the initial report that is no longer accurate 
should be updated in the EDC as well. 
8.0 Safety Monitoring Plan
All serious adverse events (SAE) (including death and hospitalization), premature withdrawal, 
and emergency treatment disclosures must be reported to the project program manager and Dr. 
Stuart at the Lahey Hospital & Medical Center Coordinating Center within one working day of 
site becoming aware of the event.  Sites will notify Dr. Stuart and project program manager via 
email at (Keith.Stuart@lahey.org) (Essence.D.Maston@lahey.org). Please include Site Name, 
Patient study ID, SAE event term, grade and pertinent de-identified source documents. Decision 
on actions to be taken for the reported SAE will be made by Dr. Stuart and the participating site 
PI. Applicable SAE forms should be completed in the electronic data capture system (EDC) 
within 5 days of their discovery of the event and updated as new information becomes available. 
9.0 Pregnancy Report 
Patients who become pregnant while on study must immediately discontinue study treatment, 
and the pregnancy must be immediately reported to the Lahey Hospital & Medical Center 
Coordinating Center. Pregnancies occurring up to 30 days after taking the last dose of the study 
drug must also be reported to the project manager at the study Coordinating Center. 
The Investigator should inform the patient of the risks of continuing with the pregnancy and the 
possible effects on the fetus. Monitoring of the patient should continue until conclusion of the 
pregnancy.
In the event of a pregnancy occurring in the partner of a male patient participating in the study, 
the participant should be requested to report the pregnancy to the investigator. The partner 
should also be informed of the risks of continuing with the pregnancy, the possible effects on the 
fetus by the participant or the treating physician. The pregnancy will be followed by the primary 
care physician or obstetrician. Even though pregnancy is not considered as SAE itself, pregnancy 
has to be reported within the timelines as defined for SAE.
10.0
Patient Discontinuation
A patient may withdraw from the study at any time and for any reason. It is intended that patients 
will be treated until investigator determined progressive disease or unacceptable toxicity. Some 
possible reasons for early discontinuation of study include, but are not limited to the following:

Occurrence of any serious adverse event

Occurrence of any serious adverse event, e.g. grade 3 or higher due to the 
chemotherapy treatment based on Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5
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 28
   


Occurrence of severe hypersensitivity reaction to anamorelin

QRS complex increases more than 15%

Development of new tumor and/or progression of pre-existing tumor

Abnormal liver function tests according to the recommendations of FDA Guidelines 
for drug-induced liver injury(https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation).

Withdrawal of consent

Investigator’s decision

Unable to receive treatments

Lost to follow-up

Pregnancy

Protocol violation

Termination of the study

Other
If a patient withdraws from the trial, a complete final evaluation at the time of the patient’s 
withdrawal should be made with an explanation of the reason for withdrawal. All patients who 
discontinue the trial as a result of an adverse event must be followed until resolution or 
stabilization of the adverse event. All patients who discontinue the trial will resume routine 
monitoring per their treating physician.
I.
STATISTICS 
All efficacy continuous variables will be analyzed via a linear model and the estimated treatment 
differences will be computed, adjusting for baseline values and the stratification factors. Binary 
variables (like responder analyses) will be analyzed using CMH models that account for the 
stratification factors.
For the primary endpoint: change from baseline in weight at week 13, the primary analysis may 
be augmented by using multiple imputations for missing data. Details of all analyses will be pre-
specified in a statistical analysis plan (SAP) that is to be completed and signed prior to database 
lock. The planned enrolment of 50 subjects per treatment arm will give 95% power to detect a 
difference of 4kg assuming a two-sided significance level of 5%, and a standard deviation of 
5.5kg.
The primary analysis will be executed for the Modified Intent-to-Treat dataset.
For all analyses, nominal p-values will be reported. If the primary endpoint shows benefit at the 
two-sided significance level of 5%, the secondary endpoints will be evaluated for providing 
significant benefit (2-sided 5%) following a hierarchal approach, using change in anorexia score 
at Week 25 as the first secondary endpoint, the change in radiologic response per RECIST 1.1 
criteria at Week 13 as the second secondary endpoint, change in patient in FACIT-F total score 
at Week 13 as the third secondary endpoint, and overall survival at week 25 as the final 
secondary endpoint.
Version 4.1: September 18January 31, 2023
 29

The expected accrual rate is 8 patients per month given that number of centers that are involved.
J.
ETHICAL AND REGULATORY ASPECTS
1.0 Ethical Considerations
The study will be performed in accordance with the principles outlined in the Declaration of 
Helsinki (23) 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.
2.0 Laws and Regulations
This clinical study will be conducted in compliance with all national laws and regulations and 
national laws and regulations of the countries in which the trial is performed.
3.0 Patient’s information sheet and informed consent form
All subjects 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 English 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. Subjects 
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 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. Remote consent or electronic informed consent is allowed for the study 
and institutional policy has to be followed for such consent process.
4.0 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. Any amendment will require 
significant justifications that explain the need to modify the existing protocol. All amendments 
will first be reviewed by the Sponsor and will subsequently be submitted to the IRB for review 
Version 4.1: September 18January 31, 2023
 30

and approval. In the event of a change that is solely administrative (e.g., a new phone number or 
email address for a study personnel), IRB will be informed via email, but will not be required to 
approve the change. 
5.0 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 unless immediate changes are necessary to protect the 
safety, rights, and welfare of the subjects. In order to obtain valid results, none of the 
investigators 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 the Sponsor as soon as possible.
6.0 Project Management and Data Collection
Lahey Hospital & Medical Center (i.e., Sponsor) staff will accomplish all the tasks necessary for 
preparation and implementation of the project, including the drafting and refinement of the study 
protocol, development of the model consent document, assisting the PI in communications, 
developing project timelines, compiling required documents, preparing the detailed operations 
manual that outlines all the tasks required for study implementation at the sites, overseeing the 
distribution of documents, updating the protocol and operations manual as needed, updating 
regulatory files for the study overall, supervising the timely renewals of IRB approvals at the 
sites, and overseeing enrollment.
6.1 Records to Be Kept
Each participating site will maintain appropriate medical and research records related to this trial 
in compliance with regulatory and institutional guidelines for the protection of subject 
confidentiality.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Examples 
of these original documents and data records include, but are not limited to hospital records, 
clinical and office records, laboratory notes, subjects’ HRQL data, radiology records, and 
treatment related records.
6.2 Data collection
Lahey Hospital & Medical Center in conjunction with Quartesian will design and distribute 
source worksheets and the electronic data capturing system
 that will maintain all data 
collected as part of the protocol. For the purposes of conducting the exploratory body 
composition analysis, a cloud-based data repository will be developed for the storage of CT/MRI 
imaging. Security features will include storage at a private secure facility, a published privacy 
policy, secure storage and transfers via secure socket layer (SSL) encryption, data back up, and 
password protected user access. The cloud-based storage will not house any identifiable PHI. 
The cloud-based storage and user access will be owned and governed by Lahey Hospital and 
Medical Center.  Additionally, Levine Cancer Institute will receive clinical trial dataset in the 
form of a Limited Dataset for the purposes of conducting the exploratory body composition 
analysis. 
Version 4.1: September 18January 31, 2023
 31

Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. Collected study data must be entered into the study EDC within 5 
days of the study visit.  Source worksheets should be used as the primary data collection 
instrument for the study, when possible.  The investigator should ensure the accuracy, 
completeness, and timeliness of the data reported in the EDC and all other required reports. Data 
reported in the EDC, that are derived from source documents, should be consistent with the 
source documents and any discrepancies should be explained. Any missing data must also be 
explained. An audit trail will be maintained by the EDC system. 
Sites are required to provide the Sponsor with de-identified source documents supporting the 
data entered into the EDC system within 1 week of each completed visit.  Source documents can 
be shared with the Sponsor via mailing, faxing, secure email and other external portal approved 
by study sites. Sites are required to provide the Sponsor with de-identified CT/MRI imaging 
within 2 weeks of each completed visit. CT/MRI imaging can be shared with the sponsor via 
upload to the secure, cloud-based data repository.  
7.0 Study Monitoring and Quality Assurance 
The site monitoring, regulatory review, adverse event reporting and quality assurance issues will 
be overseen by the Sponsor, Lahey Hospital & Medical Center.  Each site will permit authorized 
representatives of the Sponsor and regulatory agencies to examine (and when required by 
applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits and 
evaluation of the study safety and progress.  The Coordinating Center at Lahey Hospital & 
Medical Center will review and track Adverse Events, Serious Adverse Events, and Unanticipated 
Problems.
Centralized remote monitoring will be carried out 
 Center at Lahey Hospital 
& Medical Center. Monitoring will occur through periodic review of submitted source data and 
data in the EDC system.  A sample of enrolled patients may be randomly selected for a focused 
comprehensive audit of all data.  Depending on enrollment progress, the goal will be to audit a 
10% sample of enrolled patients from each site involved.  The audit will be performed by 
comparing data submitted through the EDC against source documentation submitted by the site.  
If a greater than 10% error rate is discovered, an additional 10% sample will be selected to audit. 
Additional auditing may be initiated per the Sponsor’s discretion.
8.0 Study Documentation and Records retention
The medical records of trial subjects should be retained in accordance with all applicable laws 
and in accordance with the policies of the participating institution (hospital or private entity), as 
well as with the clinical site agreement. 
Investigators/institutions at each participating site will permit trial-related IRB review and 
regulatory inspection, including direct access to source data and 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 ten (10) 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)(24) and ICH-GCP guidelines. Should there be loss of 
documentation or move of documentation, the Sponsor should be promptly notified.
Version 4.1: September 18January 31, 2023
 32
by the 

9.0 Confidentiality
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.
Version 4.1: September 18January 31, 2023
 33

K. REFERENCES
1. Centers for Disease Control and Prevention. An Update on Cancer Deaths in the United 
States [Internet]. 2020 [cited 2020 Oct 8]. Available from: 
https://www.cdc.gov/cancer/dcpc/research/update-on-cancer-deaths/index.htm
2. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. 
FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. N Engl J Med. 2011 
May 11;364(19):1817–25. 
3. Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. The Lancet. 
2011 Aug 13;378(9791):607–20. 
4. Anker MS, Holcomb R, Muscaritoli M, Haehling S von, Haverkamp W, Jatoi A, et al. 
Orphan disease status of cancer cachexia in the USA and in the European Union: a 
systematic review. Journal of Cachexia, Sarcopenia and Muscle. 2019;10(1):22–34. 
5. Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, et al. Prognostic effect of 
weight loss prior tochemotherapy in cancer patients. The American Journal of Medicine. 
1980 Oct 1;69(4):491–7. 
6. Baracos VE, Martin L, Korc M, Guttridge DC, Fearon KCH. Cancer-associated cachexia. 
Nature Reviews Disease Primers. 2018 Jan 18;4(1):1–18. 
7. Grossberg AJ, Scarlett JM, Marks DL. Hypothalamic mechanisms in cachexia. Physiology & 
Behavior. 2010 Jul 14;100(5):478–89. 
8. Basile D, Parnofiello A, Vitale MG, Cortiula F, Gerratana L, Fanotto V, et al. The IMPACT 
study: early loss of skeletal muscle mass in advanced pancreatic cancer patients. Journal of 
Cachexia, Sarcopenia and Muscle. 2019;10(2):368–77. 
9. Choi MH, Yoon SB, Lee K, Song M, Lee IS, Lee MA, et al. Preoperative sarcopenia and 
post operative accelerated muscle loss negatively impact survival after resection of 
‐
pancreatic cancer. J Cachexia Sarcopenia Muscle. 2018 Apr;9(2):326–34. 
10. Andreyev HJ, Norman AR, Oates J, Cunningham D. Why do patients with weight loss have 
a worse outcome when undergoing chemotherapy for gastrointestinal malignancies? 
European Journal of Cancer (Oxford, England: 1990). 1998 Mar;34(4):503–9. 
11. Barreto SG. Pancreatic cancer: let us focus on cachexia, not just sarcopenia! Future 
Oncology (London, England). 2018 Nov;14(27):2791–4. 
12. Solheim TS, Laird BJA, Balstad TR, Stene GB, Bye A, Johns N, et al. A randomized phase 
II feasibility trial of a multimodal intervention for the management of cachexia in lung and 
pancreatic cancer. Journal of Cachexia, Sarcopenia and Muscle. 2017 Oct;8(5):778–88. 
13. Müller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, et al. Ghrelin. 
Mol Metab. 2015 Mar 21;4(6):437–60. 
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14. Guillory B, Splenser A, Garcia J. Chapter Three - The Role of Ghrelin in Anorexia–Cachexia 
Syndromes. In: Litwack G, editor. Vitamins & Hormones [Internet]. Academic Press; 2013 
[cited 2020 Oct 8]. p. 61–106. (Anorexia; vol. 92). Available from: 
http://www.sciencedirect.com/science/article/pii/B9780124104730000039
15. Trudel L, Tomasetto C, Rio MC, Bouin M, Plourde V, Eberling P, et al. Ghrelin/motilin-
related peptide is a potent prokinetic to reverse gastric postoperative ileus in rat. American 
Journal of Physiology Gastrointestinal and Liver Physiology. 2002 Jun;282(6):G948-952. 
16. Temel JS, Abernethy AP, Currow DC, Friend J, Duus EM, Yan Y, et al. Anamorelin in 
patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): 
results from two randomised, double-blind, phase 3 trials. The Lancet Oncology. 2016 
Apr;17(4):519–31. 
17. Garcia JM, Polvino WJ. Effect on body weight and safety of RC-1291, a novel, orally 
available ghrelin mimetic and growth hormone secretagogue: results of a phase I, 
randomized, placebo-controlled, multiple-dose study in healthy volunteers. The Oncologist. 
2007 May;12(5):594–600. 
18. Garcia JM, Friend J, Allen S. Therapeutic potential of anamorelin, a novel, oral ghrelin 
mimetic, in patients with cancer-related cachexia: a multicenter, randomized, double-blind, 
crossover, pilot study. Supportive Care in Cancer: Official Journal of the Multinational 
Association of Supportive Care in Cancer. 2013 Jan;21(1):129–37. 
19. Garcia JM, Boccia RV, Graham CD, Yan Y, Duus EM, Allen S, et al. Anamorelin for 
patients with cancer cachexia: an integrated analysis of two phase 2, randomised, placebo-
controlled, double-blind trials. The Lancet Oncology. 2015 Jan 1;16(1):108–16. 
20. Takayama K, Katakami N, Yokoyama T, Atagi S, Yoshimori K, Kagamu H, et al. 
Anamorelin (ONO-7643) in Japanese patients with non-small cell lung cancer and cachexia: 
results of a randomized phase 2 trial. Supportive Care in Cancer: Official Journal of the 
Multinational Association of Supportive Care in Cancer. 2016;24(8):3495–505. 
21. Research C for DE and. E6(R2) Good Clinical Practice: Integrated Addendum to ICH 
E6(R1) [Internet]. U.S. Food and Drug Administration. FDA; 2020 [cited 2020 Oct 8]. 
Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/e6r2-good-clinical-practice-integrated-addendum-ich-e6r1
22. Common Terminology Criteria for Adverse Events (CTCAE version 5.0). 2017;147. 
23. WMA - The World Medical Association-WMA Declaration of Helsinki – Ethical Principles 
for Medical Research Involving Human Subjects [Internet]. [cited 2020 Oct 8]. Available 
from: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-
medical-research-involving-human-subjects/
24. Electronic Code of Federal Regulations (eCFR) [Internet]. Electronic Code of Federal 
Regulations (eCFR). [cited 2020 Oct 8]. Available from: https://www.ecfr.gov/
Version 4.1: September 18January 31, 2023
 35

APPENDIX 1: PROHIBITED MEDICATIONS
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
This table is not all inclusive. For the most updated lists, please refer to the FDA website at 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers
Version 4.1: September 18January 31, 2023
 36

Copyright information: The FACIT and all related works are owned and copyrighted by, and the intellectual property of David Cella, 
Ph.D. Permission for use of the FACT/FACIT system of questionnaire is obtained by contacting information@facit.org.
APPENDIX 2: FAACT- FUNCTIONAL ASSESSMENT OF ANOREXIA/CACHEXIA 
TREATMENT QUESTIONNAIRE
Below is a list of statements that other people with your illness have said are important. Please circle or mark one 
number per line to indicate your response as it applies to the past 7 days.
PHYSICAL WELL-BEING
Not 
at all
A 
little 
bit
Some
-what
Quite 
a bit
Very 
much
GP
1
I have a lack of energy…………………………
0
1
2
3
4
GP
2
I have nausea……………………………………
0
1
2
3
4
GP
3
Because of my physical condition, I have 
trouble meeting the needs of my family………..
0
1
2
3
4
GP
4
I have pain ……………………………………..
0
1
2
3
4
GP
5
I am bothered by side effects of treatment……...
0
1
2
3
4
GP
6
I feel ill………………………………………….
0
1
2
3
4
GP
7
I am forced to spend time in bed………………..
0
1
2
3
4
SOCIAL/FAMILY WELL-BEING
Not 
at all
A 
little 
bit
Some
-what
Quite 
a bit
Very 
much
GS
1
I feel close to my 
friends………………………..
0
1
2
3
4
GS
2
I get emotional support from my family………..
0
1
2
3
4
GS
3
I get support from my friends…………………..
0
1
2
3
4
GS
4
My family has accepted my illness……………..
0
1
2
3
4
GS
5
I am satisfied with family communication about 
my illness……………………………………….
0
1
2
3
4
GS
6
I feel close to my partner (or the person who is 
my main support)……………………………….
0
1
2
3
4
Version 4.1: September 18January 31, 2023
 37

Copyright information: The FACIT and all related works are owned and copyrighted by, and the intellectual property of David Cella, 
Ph.D. Permission for use of the FACT/FACIT system of questionnaire is obtained by contacting information@facit.org.
Q1
Regardless of your current level of sexual activity, 
please answer the following question. If you prefer 
not to answer it, please mark this box           and go 
to the next section.
GS
7
I am satisfied with my sex life………………….
0
1
2
3
4
EMOTIONAL WELL-BEING
Not 
at all
A 
little 
bit
Some-
what
Quite a 
bit
Very 
much
GE1
I feel sad……………………………………….
0
1
2
3
4
GE2
I am satisfied with how I am coping with my 
illness…………………………………………..
0
1
2
3
4
GE3
I am losing hope in the fight against my illness.
0
1
2
3
4
GE4
I feel nervous…………………………………..
0
1
2
3
4
GE5
I worry about dying……………………………
0
1
2
3
4
GE6
I worry that my condition will get 
worse…………………………………………..
.
0
1
2
3
4
FUNCTIONAL WELL-BEING
Not at 
all
A 
little 
bit
Some
-what
Quite 
a bit
Very 
much
GF
1
I am able to work (include work at home)……….
0
1
2
3
4
GF
2
My work (include work at home) is fulfilling……
0
1
2
3
4
GF
3
I am able to enjoy life……………………………
0
1
2
3
4
GF
4
I have accepted my illness……………………….
0
1
2
3
4
Version 4.1: September 18January 31, 2023
 38

Copyright information: The FACIT and all related works are owned and copyrighted by, and the intellectual property of David Cella, 
Ph.D. Permission for use of the FACT/FACIT system of questionnaire is obtained by contacting information@facit.org.
GF
5
I am sleeping well………………………………..
0
1
2
3
4
GF
6
I am enjoying the things I usually do for fun…….
0
1
2
3
4
GF
7
I am content with the quality of my life right now
0
1
2
3
4
ADDITIONAL CONCERNS
Not 
at all
A little 
bit
Some
-what
Quite
a bit
Very 
much
C6
I have a good appetite…………………………..
0
1
2
3
4
ACT1
The amount I eat is sufficient to meet my needs.
0
1
2
3
4
ACT2
I am worried about my weight………………….
0
1
2
3
4
ACT3
Most food tastes unpleasant to me……………...
0
1
2
3
4
ACT4
I am concerned about how thin I look………….
0
1
2
3
4
ACT6
My interest in food drops as soon as I try to eat..
0
1
2
3
4
ACT7
I have difficulty eating rich or “heavy” foods…
0
1
2
3
4
ACT9
My family or friends are pressuring me to eat…
0
1
2
3
4
O2
I have been vomiting…………………………..
0
1
2
3
4
ACT10
When I eat, I seem to get full quickly………….
0
1
2
3
4
ACT11
I have pain in my stomach area………………...
0
1
2
3
4
ACT13
My general health is improving………………...
0
1
2
3
4
Version 4.1: September 18January 31, 2023
 39

Copyright information: The FACIT and all related works are owned and copyrighted by, and the intellectual property of David Cella, 
Ph.D. Permission for use of the FACT/FACIT system of questionnaire is obtained by contacting information@facit.org.
APPENDIX 3: FACIT- FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY-
FATIGUE SUBSCALE
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.
ADDITIONAL CONCERNS
Not at 
all
A 
little 
bit
Some-
what
Quite
a bit
Very 
much
HI7
I feel fatigued………………………………………
0
1
2
3
4
HI12
I feel weak all over…………………………………
0
1
2
3
4
An1
I feel listless (“washed out”)……………………….
0
1
2
3
4
An2
I feel tired…………………………………………..
0
1
2
3
4
An3
I have trouble starting things because I am tired…..
0
1
2
3
4
An4
I have trouble finishing things because I am tired…
0
1
2
3
4
An5
I have energy……………………………………….
0
1
2
3
4
An7
I am able to do my usual activities…………………
0
1
2
3
4
An8
I need to sleep during the day……………………...
0
1
2
3
4
An12
I am too tired to eat………………………………...
0
1
2
3
4
An14
I need help doing my usual activities………………
0
1
2
3
4
An15
I am frustrated by being too tired to do the things I 
want to do…………………………………………..
0
1
2
3
4
An16
I have to limit my social activity because I am tired
0
1
2
3
4
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 40