Clinical trial NCT03274856
Conditions: Prader-Willi Syndrome
Sponsor: GLWL Research Inc.
Start date: 2018-02-20; Completion date: 2019-06-12
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The aim of this study is to evaluate efficacy, safety, and pharmacokinetics of GLWL-01 in the treatment of patients with Prader-Willi Syndrome (PWS).

Detailed description:
Participants will be assigned to one of two treatment sequences (GLWL-01/Placebo or Placebo/GLWL-01), with each sequence consisting of two treatment periods separated by a washout period

Arms: arm 1: GLWL-01 (450mg) twice a day/ Placebo arm 2: Placebo / GLWL-01 (450mg), twice a day
Interventions: intervention 1: GLWL-01 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral administration of 3 capsules, twice a day intervention 2: Oral administration of 3 capsules, twice a day

Protocol documents:
Prot_000.pdf: 
GLWL-PWS Protocol 
A Phase 2 Study to Evaluate Efficacy, Safety, and Pharmacokinetics of GLWL-01 in the 
Treatment of Patients with Prader-Willi Syndrome (Amendment d) 
NCT03274856 
Approved:  June 27, 2018


GLWL-PWS(d) Clinical Protocol 
Page 1 
GLWL-01 
Protocol GLWL-PWS(d) 
A Phase 2 Study to Evaluate Efficacy, Safety, and 
Pharmacokinetics of GLWL-01 in the Treatment of Patients 
with Prader-Willi Syndrome 
 
Confidential Information 
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of GLWL Research Inc. or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
GLWL-01, unless such persons are bound by a confidentiality agreement with GLWL 
Research Inc. or its subsidiaries.   
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  GLWL 
Research Inc. requests consultation regarding release/redaction prior to any public release.  
In the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of GLWL Research Inc. or its subsidiaries. 
GLWL-01 
 
GLWL Research Inc. 
Montreal, Quebec, Canada 
Protocol Electronically Signed and Approved by GLWL Research Inc. on date provided 
below. 
July 12, 2017 
Amendment (a):  August 17, 2017 
Amendment (b):  October 24, 2017 
Amendment (c):  June 06, 2018 
Amendment (d):  June 27, 2018 


GLWL-PWS(d) Clinical Protocol 
Page 2 
GLWL-01 
Table of Contents 
Section 
Page 
Protocol GLWL-PWS(b) A Phase 2 Study to Evaluate Efficacy, Safety, 
and Pharmacokinetics of GLWL-01 in the Treatment of Patients with 
Prader-Willi Syndrome ............................................................................................................1 
Table of Contents .............................................................................................................................2 
1. 
Synopsis ...................................................................................................................................8 
2. 
Schedule of Activities ............................................................................................................11 
3. 
Introduction ...........................................................................................................................15 
3.1. 
Study Rationale ................................................................................................................15 
3.2. 
Background.......................................................................................................................16 
3.3. 
Benefit/Risk Assessment ..................................................................................................17 
4. 
Objectives and Endpoints ......................................................................................................18 
5. 
Study Design .........................................................................................................................19 
5.1. 
Overall Design ..................................................................................................................19 
5.2. 
Number of Participants .....................................................................................................19 
5.3. 
End of Study Definition....................................................................................................20 
5.4. 
Scientific Rationale for Study Design ..............................................................................20 
5.5. 
Justification for Dose ........................................................................................................20 
6. 
Study Population ...................................................................................................................21 
6.1. 
Inclusion Criteria ..............................................................................................................21 
6.2. 
Exclusion Criteria .............................................................................................................22 
6.3. 
Lifestyle Restrictions ........................................................................................................24 
6.4. 
Screen Failures .................................................................................................................25 
7. 
Treatments .............................................................................................................................26 
7.1. 
Treatments Administered .................................................................................................26 
7.1.1. 
Packaging and Labeling ...........................................................................................26 
7.2. 
Method of Treatment Assignment ....................................................................................27 
7.2.1. 
Timing of Dose Administration ...............................................................................27 
7.3. 
Blinding ............................................................................................................................27 
7.4. 
Dosage Modification ........................................................................................................27 
7.5. 
Preparation/Handling/Storage/Accountability .................................................................28 
7.6. 
Treatment Compliance .....................................................................................................28 
7.7. 
Concomitant Therapy .......................................................................................................28 
7.8. 
Treatment after the End of the Study ...............................................................................29 
8. 
Discontinuation Criteria ........................................................................................................30 


GLWL-PWS(d) Clinical Protocol 
Page 3 
GLWL-01 
9. 
Study Assessments and Procedures .......................................................................................32 
9.1. 
Efficacy Assessments .......................................................................................................32 
9.1.1. 
Primary Efficacy Assessment – Hyperphagia Questionnaire 
for Clinical Trials .....................................................................................................32 
9.1.2. 
Secondary Efficacy Assessment – Caregiver Global 
Impression of Change ..............................................................................................32 
9.2. 
Adverse Events .................................................................................................................32 
9.2.1. 
Serious Adverse Events ...........................................................................................34 
9.2.1.1. 
Suspected Unexpected Serious Adverse Reactions ...........................................35 
9.2.2. 
Complaint Handling .................................................................................................35 
9.3. 
Treatment of Overdose .....................................................................................................35 
9.4. 
Safety ................................................................................................................................35 
9.4.1. 
Electrocardiograms ..................................................................................................35 
9.4.2. 
Vital Signs ................................................................................................................36 
9.4.3. 
Laboratory Tests ......................................................................................................36 
9.4.4. 
Columbia Suicide-Severity Rating Scale .................................................................36 
9.4.5. 
Safety Monitoring ....................................................................................................37 
9.4.5.1. 
Hepatic Safety Monitoring .................................................................................37 
9.5. 
Pharmacokinetics ..............................................................................................................37 
9.5.1. 
Blood Sampling and Processing ..............................................................................37 
9.5.2. 
Bioanalytical Method ...............................................................................................38 
9.6. 
Pharmacodynamics ...........................................................................................................38 
9.6.1. 
Acylated-Ghrelin and Unacylated-Ghrelin ..............................................................38 
9.7. 
Biomarkers .......................................................................................................................38 
9.8. 
Health Economics .............................................................................................................38 
10. Statistical Considerations ......................................................................................................39 
10.1. Sample Size Determination ..............................................................................................39 
10.2. Populations for Analyses ..................................................................................................39 
10.3. Statistical Analyses ...........................................................................................................39 
10.3.1. 
General Statistical Considerations ...........................................................................39 
10.3.2. 
Treatment Group Comparability ..............................................................................40 
10.3.2.1. 
Patient Disposition .............................................................................................40 
10.3.2.2. 
Patient Characteristics ........................................................................................40 
10.3.2.3. 
Concomitant Therapy .........................................................................................40 
10.3.2.4. 
Treatment Compliance .......................................................................................40 
10.3.3. 
Efficacy Analyses ....................................................................................................40 
10.3.3.1. 
Primary Analyses ...............................................................................................40 
10.3.3.2. 
Secondary Analyses ...........................................................................................40 


GLWL-PWS(d) Clinical Protocol 
Page 4 
GLWL-01 
10.3.3.3. 
Exploratory Analyses .........................................................................................40 
10.3.4. 
Safety Analyses ........................................................................................................41 
10.3.5. 
Pharmacokinetic/Pharmacodynamic Analyses ........................................................42 
10.3.6. 
Evaluation of Immunogenicity .................................................................................42 
10.3.7. 
Interim Analyses ......................................................................................................43 
11. References .............................................................................................................................44 
12. Appendices ............................................................................................................................46 
 


GLWL-PWS(d) Clinical Protocol 
Page 5 
GLWL-01 
List of Tables 
Table 
Page 
Table GLWL-PWS.1. 
Schedule of Activities ............................................................................12 
Table GLWL-PWS.2. 
Objectives and Endpoints .......................................................................18 
 
 
 


GLWL-PWS(d) Clinical Protocol 
Page 6 
GLWL-01 
List of Figures 
Figure 
Page 
Figure GLWL-PWS.1. Illustration of study design for Clinical Protocol GLWL-PWS. ...........19 
 
 
 


GLWL-PWS(d) Clinical Protocol 
Page 7 
GLWL-01 
List of Appendices 
Appendix 
Page 
Appendix 1. 
Abbreviations and Definitions ...........................................................................47 
Appendix 2. 
Clinical Laboratory Tests ..................................................................................50 
Appendix 3. 
Study Governance Considerations ....................................................................51 
Appendix 4. 
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ....................54 
Appendix 5. 
Sampling Summary ...........................................................................................55 
Appendix 6. 
Protocol Amendment GLWL-PWS(a) Summary [A Phase 2 Study to 
Evaluate Efficacy, Safety, and Pharmacokinetics of GLWL-01 in the 
Treatment of Patients with Prader-Willi Syndrome] .........................................56 
Appendix 7. 
Protocol Amendment GLWL-PWS(b) Summary [A Phase 2 Study to 
Evaluate Efficacy, Safety, and Pharmacokinetics of GLWL-01 in the 
Treatment of Patients with Prader-Willi Syndrome] .........................................67 
Appendix 5. Sampling Summary ...................................................................................................81 
Appendix 8. 
Protocol Amendment GLWL-PWS(c) Summary [A Phase 2 Study to 
Evaluate Efficacy, Safety, and Pharmacokinetics of GLWL-01 in the 
Treatment of Patients with Prader-Willi Syndrome] .........................................82 
Appendix 9. 
Protocol Amendment GLWL-PWS(d) Summary [A Phase 2 Study to 
Evaluate Efficacy, Safety, and Pharmacokinetics of GLWL-01 in the 
Treatment of Patients with Prader-Willi Syndrome] .........................................87 
 


GLWL-PWS(d) Clinical Protocol 
Page 8 
GLWL-01 
1. Synopsis 
Title of Study: 
A Phase 2 Study to Evaluate Efficacy, Safety, and Pharmacokinetics of GLWL-01 in the 
Treatment of Patients with Prader-Willi Syndrome (PWS)  
Rationale:  
The aim of this study is to evaluate efficacy, safety, and pharmacokinetics of GLWL-01 in the 
treatment of patients with Prader-Willi Syndrome (PWS).  
Objectives/Endpoints: 
Objectives 
Endpoints 
Primary 
• Evaluate the efficacy of GLWL-01 compared 
with placebo in reducing hyperphagia-related 
behaviors after 28 days of treatment in 
patients with PWS as measured using the 
Hyperphagia Questionnaire for Clinical Trials 
(HQ-CT) 
 
• 
Posttreatment HQ-CT total score 
Secondary 
• 
Evaluate the safety and tolerability of 
GLWL-01 after 28 days of treatment in 
patients with PWS 
• 
Evaluate the efficacy of GLWL-01 compared 
with placebo in reducing hyperphagia-related 
behaviors after 28 days of treatment in 
patients with PWS as measured using the 
Caregiver Global Impression of Change 
(CGIC) 
• 
Evaluate the pharmacokinetics after single and 
multiple oral dosing of GLWL-01 in patients 
with PWS 
 
• 
Treatment-emergent adverse events 
 
 
• 
CGIC score 
 
 
 
 
• 
GLWL-01 
o 
Area under the concentration versus time 
curve from time zero to 12 hours (AUC0-12) 
o 
Maximum observed drug concentration 
(Cmax) 
Exploratory 
• 
Evaluate the effect of GLWL-01 in the 
following measures in patients with PWS 
• 
Acylated-ghrelin (AG) 
• 
Unacylated-ghrelin (UAG) 
• 
AG/UAG ratio 
• 
Body weight 
• 
Percentage fat mass 
• 
Body mass index 
• 
Waist circumference 
• 
Low-density lipoproteins 
• 
Total cholesterol 
 
 
Posttreatment: 
• 
AG 
• 
UAG 
• 
AG/UAG 
• 
Body weight 
• 
Percentage fat mass 
• 
Body mass index 
• 
Waist circumference 
• 
Low-density lipoproteins 
• 
Total cholesterol 
 
 
 


GLWL-PWS(d) Clinical Protocol 
Page 9 
GLWL-01 
Summary of Study Design:   
Study GLWL-PWS is a multicenter, double-blind, randomized, placebo-controlled, crossover 
study of GLWL-01 in patients with PWS.  
The study consists of 5 periods, including 2 active treatment periods, as depicted below: 
Period 
Phase 
Duration 
Screening  
NA 
28 days 
Treatment Period 1 
Single-blind placebo lead-ina 
14 days 
 
Double-blind treatment phaseb 
28 days 
Washout 
NA 
28 days 
Treatment Period 2 
Single-blind placebo lead-ina 
14 days 
 
Double-blind treatment phaseb 
28 days 
Follow-up 
NA 
14 days 
Abbreviation:  NA = not applicable 
a Only patient/caregiver will be blinded. 
b Both investigator and patient/caregiver will be blinded. 
 
Patients and caregivers will be required to visit the site on 8 occasions at Visits 1, 3, 4, 5, 8, 9, 
10, and 11.  Patients and caregivers will be required to participate in phone calls with the site at 
Visits 2, 6, and 7. 
Treatment Arms and Duration: 
Patients will be randomized to 1 of 2 treatment sequences; GLWL-01/placebo or 
placebo/GLWL-01 (Treatment Period 1 double-blind treatment phase/Treatment Period 2 
double-blind treatment phase).  During single-blind placebo lead-in phases, patients will receive 
3 capsules of 150-mg placebo twice daily (BID) for 14 days.  During double-blind treatment 
phases, patients will receive 3 capsules of 150-mg GLWL-01 (450 mg total dose) BID or 
identical placebo BID for 28 days. 
Number of Patients:  
Approximately 34 patients with PWS will be randomized.  
Statistical Analysis: 
Efficacy:  Efficacy analyses will be conducted on the randomized analysis set.  The primary 
analysis will be conducted using a restricted maximum likelihood-based, mixed-effect model 
repeated measures analysis.  The analysis will be the contrast between GLWL-01 and placebo at 
the end of the double-blind treatment phase on the primary endpoint of the posttreatment HQ-CT 
score. 
The secondary analysis will be conducted similar to the primary analysis.  The secondary 
efficacy endpoint is the CGIC. 
Safety:  Safety analyses will be conducted on the safety analysis set.  Safety data will be 
summarized by treatment group.  Safety parameters that will be assessed include adverse events, 


GLWL-PWS(d) Clinical Protocol 
Page 10 
GLWL-01 
clinical laboratory parameters, C-SSRS, vital signs, electrocardiogram parameters, and weight.  
The parameters will be listed and summarized using standard descriptive statistics. 
Pharmacokinetics/Pharmacodynamics:  Plasma GLWL-01 pharmacokinetic (PK) parameters will 
be calculated using noncompartmental methods after single and multiple dose administration.  
Additional PK parameters may be calculated if deemed appropriate.  Pharmacokinetic 
parameters will be summarized by dose level using descriptive statistics.  Mean and individual 
GLWL-01 plasma concentration-time curves will be represented graphically. 
Pharmacodynamics of GLWL-01 will be based on plasma AG and potentially UAG measures.  
Raw and change from baseline values will be reported and summarized for AG and potentially 
UAG. 
The PK/PD relationship of GLWL-01 with PD, efficacy, and/or safety measures may be 
explored. 
 
 
 
 


GLWL-PWS(d) Clinical Protocol 
Page 11 
GLWL-01 
2. Schedule of Activities 
 


GLWL-PWS(d) Clinical Protocol 
Page 12 
GLWL-01 
Table GLWL-PWS.1. Schedule of Activities  
Period 
Screeninga 
Treatment Period 1 
Washout 
(28 days) 
Treatment Period 2 
Follow-up 
ETc 
Phase 
 
Single-blind 
Placebo 
Lead-in 
Phase 
(14 days) 
Double-blind 
Treatment Phase 
(28 days)b 
 
Single-blind 
Placebo 
Lead-in 
(14 days) 
Double-blind 
Treatment Phase 
(28 days)b 
 
Visit No/ 
Type Procedure 
V1 
 
V2e 
Phone 
V3d 
 
V4  
 
V5 
 
V6 e 
Phone 
V7e 
Phone 
V8 
 
V9  
 
V10 
 
V11 
 
Day  
-28 to -3 
0 
(±3) 
14 
(±2) 
21 
(±2) 
42 
(±2) 
56 
(±2) 
70 
(±2) 
84 
(±2) 
91 
(±2) 
112 
(±2) 
126  
(±3) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationf 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Heightg 
X 
 
 
 
 
 
 
 
 
 
 
 
Initial history/ preexisting conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAg, HCAB, HIV  
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysish 
X 
 
 
 
 
 
 
 
 
 
 
 
Substance abuse screeni 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion review 
X 
 
Xe 
 
 
 
 
 
 
 
 
 
Study drug dispensing 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
Study drug administration at site 
 
 
X 
 
X 
 
 
 
 
 
 
 
Study drug accountability 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Efficacy and Outcome Measures 
HQ-CT 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGIC 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Body weightg 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Percentage fat mass (calipers) 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
BMI 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Waist circumference 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Vital signsj 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 


GLWL-PWS(d) Clinical Protocol 
Page 13 
GLWL-01 
Period 
Screeninga 
Treatment Period 1 
Washout 
(28 days) 
Treatment Period 2 
Follow-up 
ETc 
Phase 
 
Single-blind 
Placebo 
Lead-in 
Phase 
(14 days) 
Double-blind 
Treatment Phase 
(28 days)b 
 
Single-blind 
Placebo 
Lead-in 
(14 days) 
Double-blind 
Treatment Phase 
(28 days)b 
 
Visit No/ 
Type Procedure 
V1 
 
V2e 
Phone 
V3d 
 
V4  
 
V5 
 
V6 e 
Phone 
V7e 
Phone 
V8 
 
V9  
 
V10 
 
V11 
 
Day  
-28 to -3 
0 
(±3) 
14 
(±2) 
21 
(±2) 
42 
(±2) 
56 
(±2) 
70 
(±2) 
84 
(±2) 
91 
(±2) 
112 
(±2) 
126  
(±3) 
12-lead ECGk 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
12-lead ECG 2 hours post-dose k 
 
 
X 
 
 
 
 
X 
 
 
 
 
Serum pregnancy testl 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Urine pregnancy testl 
 
 
X 
 
 
 
 
X 
 
 
 
 
Clinical chemistry and hematologyh 
X 
 
X 
X 
X 
 
 
X 
X 
X 
 
X 
Troponin 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
Lipid panel 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
AG and UAGm 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Plasma sample collection for PK 
analysisn 
 
 
X 
 
X 
 
 
 
 
 
 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations:  AE = adverse event; AG = acylated-ghrelin; BMI = body mass index; CGIC = Caregiver Global Impression of Change; C-SSRS = Columbia–Suicide Severity 
Rating Scale; ECG = electrocardiogram; EDC = electronic data capture; ET = early termination; HQ-CT = Hyperphagia Questionnaire for Clinical Trials; HBsAg = hepatitis B 
surface antigen; HCAB = hepatitis C antibody; HIV = human immunodeficiency virus; PK = pharmacokinetic; UAG = unacylated-ghrelin; V = Visit. 
a 
Screening visit must occur between -28 days to -3 days of V2. 
b 
Double-blind Treatment Phase must not exceed 28 days and patients must not take the study drug beyond 28 days.  For example, if the V3 occurs on Day 14, then 
corresponding V5 would occur on Day 42.  Similarly, if V3 occurs on Day 15 (Day 14 +1), then corresponding V5 would occur on Day 43 (Day 42 +1).  
c 
The primary reason for early termination of the patient will be entered in EDC and recorded in the patient’s source documents.  The patient will attend an early termination visit 
as soon as possible after participation ceases. 
d 
Confirm that the patient has met all inclusion/exclusion criteria.  Patients will only be dosed after the investigator has completed the appropriate protocol assessments and 
determined that it is acceptable to dose the patient. 
e 
Patients/caregivers will receive phone calls from the site; no visit required.  Both patient and caregiver should be on the phone in order for the site to conduct AE assessments 
and the C-SSRS. 


GLWL-PWS(d) Clinical Protocol 
Page 14 
GLWL-01 
f 
A full physical examination with neurological assessments should be performed at Visit 1.  Symptom-driven physical examinations should be performed at V3, V4, V5, and 
V8, V9, V10,V11, and at ET.  
g 
Height will only be measured at Visit 1.  Patients should be instructed to wear lightweight clothing and remove shoes during weighing.   
h 
Refer to Appendix 2 for details on serum chemistry, hematology, and urinalysis clinical laboratory tests. 
i 
Substance abuse screen test to be performed at Visit 1 and additionally at any visit per investigator’s discretion. 
 
j 
Vital sign assessments will include triplicate sitting blood pressure, and single pulse and body temperature.  Additional vital sign assessments may be performed as clinically 
indicated.  For visits in which both vital signs and blood samples are collected, vital signs should be obtained prior to blood collection.  Any clinically significant result of vital 
sign assessment will be documented in the source documentation and EDC as an AE. 
k 
Single 12-lead ECGs to be collected according to the schedule and may be collected at any time if deemed clinically necessary.  Patients must be supine for at least 5 minutes 
prior to ECG collection.  When ECG collections are scheduled at the same time point as any other tests, ECGs, followed by vital signs, should be recorded prior to any clinical 
laboratory or PK blood sampling. 
l 
For all female patients, the investigator will document potential childbearing status.  For women who are postmenopausal, a confirmatory test of serum follicule-stimulating 
hormone and estradiol levels will be done at Visit 1.  For all women of childbearing potential, a pregnancy serum test will be done at Visit 1, which must be negative to enroll.  
Subsequently, urine pregnancy tests will be done for all women of childbearing potential as indicated in the schedule; the results must be confirmed negative.  In case of a 
positive urine pregnancy test, the serum pregnancy test must be performed to confirm the pregnancy results. 
m The blood samples for AG and UAG should be collected in the fasted state. 
n 
On Day 14 and Day 42, a total of 7 PK samples each day will be taken at the following times:  pre-dose, and 0.5, 1, 2, 4, 6, and between 8 and 12 hours postdose.  Times of 
sampling are intended as a guide and can be modified to accommodate clinical procedures.  Actual time of sample must be collected, as well as date and time of dosing on the 
day of PK sample collection.  For patients who discontinue early, a sample should be obtained at the ET visit.  
 
 
 


GLWL-PWS(d) Clinical Protocol 
Page 15 
GLWL-01 
3. Introduction 
3.1. Study Rationale 
The aim of this study is to evaluate efficacy, safety, and pharmacokinetics (PK) of GLWL-01 in 
patients with Prader-Willi syndrome (PWS).  The trial will be conducted in compliance with the 
protocol, good clinical practice (GCP), and applicable regulatory requirements.  The patient 
population will be comprised of adolescent (aged 16 to 18 years) and adult (aged >18 to 
65 years) male and female patients with PWS. 
Prader-Willi syndrome is a complex, rare genetic disorder that affects appetite, growth, 
metabolism, cognitive function, and behavior.  It is caused by a spontaneous genetic error that 
leads to a lack of expression of paternal genes on chromosome 15.  In a majority of the cases 
(about 75%), there is a deletion of paternal genes (15q11-q13).  In most of the remaining cases, 
the 2 copies of chromosome 15 originate from the mother (maternal uniparental disomy; PWSA 
USA Resource Page; The University of Chicago Resource Page).  Paternally expressed genes are 
crucial for hypothalamic development and their lack of expression causes hypothalamic 
dysfunction; this ultimately results in problems with hunger, growth, sexual development, body 
temperature, mood, and sleep (Goldstone 2004). 
Patients with PWS exhibit gross hyperphagia behaviors that are triggered by a constant feeling of 
hunger.  As a result, these patients have difficulty keeping their weight under control and suffer 
from complications of obesity (such as type 2 diabetes, high blood pressure (BP), high levels of 
cholesterol, heart disease, and sleep apnea) and from inadequate hormone production (sterility, 
osteoporosis).  
To our knowledge, there are no approved therapies that would obviate the need for a strict 
externally controlled diet and limited access to food for these patients (PWSA USA Resource 
Page).  Treatments use a multifaceted approach including diet management, hormones (human 
growth hormone, sex hormones), sleep apnea treatment, mental healthcare, and behavioral 
therapies.  
Ghrelin is secreted primarily by the stomach and circulates as both acylated (AG) and 
unacylated-ghrelin (UAG).  Acylated-ghrelin stimulates appetite, and AG concentrations are 
elevated in PWS (Kuppens et al. 2015), suggesting that AG may contribute to hyperphagia and 
obesity in these patients.  
GLWL-01 is an inhibitor of the ghrelin-O-acyltransferase (GOAT) enzyme that converts UAG 
into AG.  In a previous clinical study (GLWL-SMP; Clinicaltrials.gov identifier NCT02377362) 
in obese patients with type 2 diabetes, GLWL-01 doses ≥150 mg twice a day (BID) given over 
28 days have shown a numerical decrease in plasma AG concentrations.  In the same study, 
doses of GLWL-01 up to 600 mg BID for 28 days were generally well tolerated.  Therefore, it is 
of interest to assess the efficacy of GLWL-01 compared with placebo in reducing 
hyperphagia-related behaviors through 28 days in patients with PWS. 


GLWL-PWS(d) Clinical Protocol 
Page 16 
GLWL-01 
3.2. Background 
Acylated ghrelin plays a pivotal role in metabolism and energy balance and is the only known 
orexigenic peptide hormone in human and mammals (Chen et al. 2009; Callaghan and 
Furness 2014).  Acylated-ghrelin regulates short-term energy homeostasis by increasing hunger 
and food intake and long-term energy balance by promoting weight gain and adiposity 
(Tschop et al. 2000; Wren et al. 2001a; Wren et al. 2001b; Cummings et al. 2004).  All these 
actions are believed to be mediated in part through its binding to growth hormone secretagogue 
receptor (GHSR-1a).  Unacylated ghrelin is the only known physiological substrate of the GOAT 
enzyme.  It has been shown that UAG counters the hyperglycemic effect of AG in healthy 
human volunteers when it is co-administered with AG.  Infusion of UAG lowers average blood 
glucose levels, enhances insulin secretion, and reduces free fatty acids in plasma in healthy 
human volunteers (Benso et al. 2012).  The mechanisms responsible for these actions are unclear 
as UAG binds to the GHSR-1a receptor with 1000-fold lower affinity than AG. 
Prader-Willi syndrome is a neurogenetic disorder that is characterized by severe morbid obesity 
related to hyperphagia (Kuppens et al. 2015).  Due to AG’s well-known association with hunger, 
food intake, and weight gain, it is suggested that hyperphagia in PWS might be subsequent to 
increased ghrelin levels (Purtell et al. 2011; Kweh et al. 2015).  Since UAG acts as a functional 
inhibitor of AG and that it suppresses ghrelin levels in humans, ratio of AG and UAG levels 
(AG/UAG ratio) could play a crucial role in maintaining the weight balance.  
A clinical study conducted in 3 PWS expert centers in the Netherlands and France compared AG 
and UAG levels, and the AG/UAG ratio, in patients with PWS (n=138, 0.2 to 29.4 years), obese 
subjects (n=50; 4.3 to 16.9 years), and healthy control subjects (n=39, 0.8 to 28.6 years).  
Concentrations of AG were higher in PWS compared to healthy control subjects, while UAG 
was similar to that of control subjects.  Both AG and UAG were significantly lower in the obese 
group than for PWS and control subjects.  These differences in AG and UAG concentrations 
were reflected in elevated AG/UAG ratios in patients with PWS who exhibited weight gain 
and/or hyperphagia; while those without weight gain or hyperphagia had ratios comparable to 
those of age-matched control subjects.  The authors proposed that the switch to excessive weight 
gain in PWS appears to coincide with an increase in the AG/UAG ratio, even preceding 
hyperphagia (Kuppens et al. 2015). 
These AG and UAG data are overall consistent with a multiple ascending dose study of 
GLWL-01 in overweight and obese adult patients with type 2 diabetes (n=38), which showed a 
decrease in AG without weight loss, and low UAG concentrations.  Since hyperphagia behaviors 
may be linked to elevated AG concentrations in patients with PWS, GLWL-01 may lower 
elevated AG concentrations and thus reduce hyperphagia behaviors. 
GLWL-01 is a small molecule inhibitor of GOAT, which is superficially expressed primarily in 
the stomach and pancreas of humans and rats.  GLWL-01 is the first GOAT inhibitor being 
clinically evaluated for the treatment of PWS.  Inhibition of GOAT is expected to lower AG and 
raise UAG plasma levels.  


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
GLWL-01 is a potent inhibitor of human GOAT with an IC50 of 192 nM in a primary enzyme 
assay and of 8.20 nM in a cell-based assay.  In the nonclinical pharmacology studies, GLWL-01 
demonstrated dose-dependent reduction in AG concentrations and increases in UAG 
concentrations (GLWL-01 2017).  
Based on PK data in healthy subjects, both renal clearance and hepatic metabolism are involved 
in the clearance of GLWL-01 (GLWL-01 2017).  In a multiple-dose study in obese patients with 
type 2 diabetes (GLWL-SMP), GLWL-01 exposure (based upon maximum observed drug 
concentration [Cmax] and area under the concentration versus time curve (AUC) generally 
increased in a higher than dose-proportional manner with increasing doses of GLWL-01 (dose 
range:  50 to 600 mg BID and 300 to 450 mg once daily [QD]).  Median time of maximum 
observed drug concentration values ranged from approximately 1 to 2 hours on Day 1, and on 
Day 28, ranged from approximately 1 to 4.5 hours, with an apparent trend of increasing with 
dose on Day 28.  Mean values of half-life associated with the terminal rate constant in 
noncompartmental analysis were relatively short (approximately 3 to 6 hours).  
3.3. Benefit/Risk Assessment 
Based on GLWL-01 nonclinical and preliminary clinical data, there are no anticipated risks 
requiring monitoring beyond those included in this protocol.  No clinically significant safety or 
tolerability concerns have been identified in patients or subjects to date for GLWL-01 up to the 
highest single dose given 600 mg in healthy subjects and multiple dose given 600 mg BID for up 
to 28 days in obese patients with type 2 diabetes.  
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of GLWL-01 can be found in the Investigator’s 
Brochure (IB; GLWL-01 2017). 
 


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GLWL-01 
4. Objectives and Endpoints 
Table GLWL-PWS.2 shows the objectives and endpoints of the study. 
Table GLWL-PWS.2. Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
Evaluate the efficacy of GLWL-01 compared 
with placebo in reducing hyperphagia-related 
behaviors after 28 days of treatment in 
patients with PWS as measured using the 
HQ-CT 
 
• 
Posttreatment HQ-CT total score 
 
 
Secondary 
• 
Evaluate the safety and tolerability of 
GLWL-01 after 28 days of treatment in 
patients with PWS 
• 
Evaluate the efficacy of GLWL-01 compared 
with placebo in reducing hyperphagia-related 
behaviors after 28 days of treatment in 
patients with PWS as measured using the 
CGIC 
• 
Evaluate the pharmacokinetics after single and 
multiple oral dosing of GLWL-01 in patients 
with PWS 
 
• 
Treatment-emergent adverse events 
 
 
• 
CGIC score 
 
 
 
 
• 
GLWL-01 
o 
AUC0-12  
o 
Cmax 
Exploratory 
Evaluate the effect of GLWL-01 in the following 
measures in patients with PWS: 
• 
AG 
• 
UAG 
• 
AG/UAG ratio 
• 
Body weight 
• 
Percentage fat mass 
• 
Body mass index 
• 
Waist circumference 
• 
Low-density lipoproteins 
• 
Total cholesterol 
 
 
Posttreatment: 
• 
AG 
• 
UAG 
• 
AG/UAG ratio 
• 
Body weight 
• 
Percentage fat mass 
• 
Body mass index 
• 
Waist circumference 
• 
Low-density lipoproteins 
Total cholesterol 
Abbreviations:  AG = acylated-ghrelin; AUC0-12 = area under the concentration versus time curve from time zero to 
12 hours; CGIC = Caregiver Global Impression of Change; Cmax = maximum observed drug concentration; HQ-CT 
= Hyperphagia Questionnaire for Clinical Trials; PWS = Prader-Willi syndrome; UAG = unacylated-ghrelin. 
 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
5. Study Design 
5.1. Overall Design 
This is a multicenter, double-blind, randomized, placebo-controlled, crossover study to evaluate 
the efficacy of GLWL-01 in patients with PWS.  The study consists of 5 periods, including 
2 active treatment periods, as depicted below:  
 
Abbreviations:  P = phone visit; PK = pharmacokinetic sample 
Note:  Placebo lead-in phases will be single-blinded (patient/caregiver) and treatment phases will be double-blinded 
(investigator and patient/caregiver) 
Figure GLWL-PWS.1. Illustration of study design for Clinical Protocol GLWL-PWS. 
The Screening Period allows for evaluation of inclusion/exclusion criteria.  Treatment Period 1 
consists of 2 phases:  a 14-day single-blind (patient/caregiver) placebo lead-in phase followed by 
a 28-day double-blind treatment phase.  At the conclusion of the single-blind placebo lead-in 
phase, eligible patients will be randomly assigned (in 1:1 ratio) to 1 of 2 treatment sequences:  
GWLW-01/placebo or placebo/GLWL-01 (Treatment Period 1 double-blind treatment 
phase/Treatment Period 2 double-blind treatment phase).  Following Treatment Period 1, there 
will be a 28-day Washout Period.  Treatment Period 2 also consists of 2 phases:  a 14-day 
single-blind (patient/caregiver) placebo lead-in followed by a 28-day double-blind treatment 
phase.  Following Treatment Period 2, there will be a 14-day Follow-up Period (see 
Figure GLWL-PWS.1). 
Patients and caregivers will be required to visit the site on 8 occasions at Visits 1, 3, 4, 5, 8, 9, 
10, and 11; Patients and caregivers will be required to participate in phone calls with the site at 
Visits 2, 6, and 7. 
Study governance considerations are described in detail in Appendix 3. 
5.2. Number of Participants 
Approximately 34 patients will be randomized 1:1 to 1 of 2 treatment sequences 
(GLWL-01/placebo or placebo/GLWL-01).  


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GLWL-01 
5.3. End of Study Definition 
End of the study is the date of the last Follow-up Visit or End-of-Treatment/Discontinuation 
Visit shown in the Schedule of Activities (Section 2) for the last patient to complete or 
discontinue the study. 
5.4. Scientific Rationale for Study Design 
The use of a crossover design allows each patient to serve as his or her own control, thereby 
reducing variability.  The single-blind placebo lead-in phase for Treatment Period 1 is included 
to minimize potential bias in completing the Hyperphagia Questionnaire for Clinical Trials 
(HQ-CT) by the caregiver.  The single-blind placebo lead-in phase for Treatment Period 2 is 
included to minimize potential bias in completing the HQ-CT by the caregiver and control for 
period effect.  The washout period will allow for GLWL-01 to be eliminated from the body, 
based on the known GLWL-01 half-life, and to account for any potential behavioral changes 
from Treatment Period 1.  The study is patient-/caregiver- and investigator-blind to minimize 
potential bias during the double-blind treatment phases.  
5.5. Justification for Dose 
Administration of single GLWL-01 doses of up to 600 mg QD in healthy subjects, and of 
multiple (up to 28 days) GLWL-01 doses of up to 600 mg BID in obese patients with type 2 
diabetes was safe and generally well tolerated (GLWL-SMP study).  Doses of GLWL-01 equal 
to or higher than 150 mg BID resulted in numerical decreases of plasma AG levels in obese 
patients with type 2 diabetes over 28 days, with the maximum decreases observed for the 450-mg 
BID dose group.  Therefore, a 450-mg BID dosing regimen was chosen for this study as it has 
been demonstrated to be safe and to achieve target engagement. 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
6. Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
6.1. Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all of the following criteria at 
screening: 
1. Male and female outpatients between 16 and 65 years of age inclusive, prior to signing 
informed consent. 
2. Confirmed diagnosis of PWS based on genetic confirmation using DNA methylation test. 
3. Body mass index (BMI) of 27 to 60 kg/m2, inclusive, at Visit 1.   
4. No evidence of weight excursion beyond 10% of baseline weight within 3 months prior to 
Visit 1 (self- or caregiver-reported). 
5. Patients must provide assent and have a reliable caregiver (must have been caring for the 
patient for at least 6 months) who provides a separate written informed consent to 
participate.  The caregiver is expected to be the primary caregiver throughout the study and 
must be in frequent contact with the patient (defined as at least 4 awake hours per day).  The 
caregiver must be able to communicate with site personnel and in the investigator’s opinion 
must have adequate literacy to complete the protocol-specified questionnaires.  If a 
caregiver cannot continue, 1 caregiver replacement is allowed. 
6. Male patients: 
a. agree to use a reliable method of birth control during the study and 3 months 
following the last dose of the study drug.  Acceptable methods of birth control 
may include:  1) condom with spermicide; 2) diaphragm with spermicide; or 3) 
female condom with spermicide. 
7. Female patients: 
a. Women of child-bearing potential may participate in the study if they test 
negative for pregnancy (based on a serum pregnancy test) prior to initiation of 
treatment.  They must also agree to use either 1 highly effective method of 
contraception or a combination of 2 effective methods of contraception during the 
study.   
Highly effective method may include hormonal contraceptives (e.g., 
combined oral contraceptives, patch, vaginal ring, injectables, and 
implants); intrauterine device or intrauterine system; vasectomy and tubal 
ligation. 
Effective methods may include barrier methods of contraception (e.g., male 
condom, female condom, cervical cap, diaphragm, contraceptive sponge). 
Women may choose to use a double-barrier method of contraception.  Barrier 
methods without concomitant use of a spermicide are not reliable or an acceptable 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
method.  Thus, each barrier method must include use of a spermicide.  It should be 
noted that the use of male and female condoms as a double-barrier method is not 
considered acceptable due to the high failure rate when these methods are combined. 
 
• Women not of child-bearing potential may participate in the study and include those who 
have 
a. spontaneous amenorrhea for at least 12 months, not induced by a medical 
condition such as anorexia nervosa and not taking medications that induced 
amenorrhea (e.g., oral contraceptives, hormones, gonadotropin-releasing 
hormone, anti-estrogens, selective estrogen receptor modulators, or 
chemotherapy; or 
b. spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone 
(FSH) level greater than 40 mIU/mL; or 
c. women with a history of hysterectomy or bilateral oophorectomy must be at least 
40 years of age and FSH >40 mIU/mL. 
8. Are on a stable diet and exercise regimen for >2 months prior to Visit 1. 
6.2. Exclusion Criteria 
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening: 
9. Are Eli Lilly and Company, GLWL Research Inc. (sponsor hereafter), contract research 
organization employees, investigator or site personnel directly affiliated with this study and 
their immediate families.  Immediate family is defined as a spouse, parent, child or sibling, 
whether biological or legally adopted. 
10. Are currently enrolled in any other clinical trial involving a study drug or off-label use of a 
drug or device, or any other type of medical research judged not to be scientifically or 
medically compatible with this study.  
11. Participated in a clinical trial within 30 days (defined as last dose of study drug), prior to the 
GLWL-PWS first dose.  
12. Are currently living in a group home for more than 50% of the time. 
13. Have a HQ-CT total score at Visit 3 <13. 
14. Have clinical laboratory test results outside normal reference range, or any clinically 
significant laboratory abnormality, that in the judgment of the investigator, indicates a 
medical problem that would preclude study participation.  Values for aspartate 
aminotransferase (AST)/alanine aminotransferase (ALT)/gamma-glutamyl transferase 
(GGT)/alkaline phosphatase (ALP) >3X upper limit of normal (ULN). 
15. Have an estimated glomerular filtration rate <60 mL/minute/1.73 m2.  Have 
macroalbuminuria (defined as spot urine albumin to creatinine ratio of >300 µg/mg) or 
hematuria. 
16. Are hypertensive (defined as sitting systolic BP ≥140 mmHg and diastolic BP ≥90 mmHg) 
on or off medications for the treatment of hypertension.  Blood pressure may be re-tested up 
to 2 additional times, under well-rested conditions. 


GLWL-PWS(d) Clinical Protocol 
Page 23 
GLWL-01 
17. In addition to conditions described below, have a history or presence of any other medical 
illness including but not limited to any autoimmune disorder, cardiovascular, hepatic, 
respiratory, hematological, or uncontrolled neurological disease. 
a. Have a history of clinically overt uncontrolled or untreated endocrine illness 
such as growth hormone insufficiency, adrenal gland, or thyroid illness. 
b. Have evidence of other chronic liver disease, including but not limited to 
chronic alcoholic disease, cirrhosis of any cause, recent history (within 3 
months of screening) of acute viral hepatitis or chronic autoimmune hepatitis.  
Patients with a history of biliary disease, including primary sclerosing 
cholangitis, must be excluded.  Patients with a history of cholecystectomy 
longer than 6 months prior to screening could be enrolled. 
c. Have evidence of significant active or unstable/uncontrolled psychiatric 
disease by medical history, such as bipolar disorder, schizophrenia, 
personality disorders, or other serious mood or anxiety disorders.  Note:  
Patients whose disease state is considered stable and expected to remain stable 
throughout the course of the study, in the opinion of the investigator, may be 
considered for inclusion if they are not on excluded medications. 
18. Have an abnormality in the 12-lead electrocardiogram (ECG), including corrected QT 
interval with Frederica’s correction (QTcF) >450 msec for men and >470 msec for women 
or an abnormality that, in the opinion of the investigator, increases the risks associated with 
participating in the study.  If QTcF does not meet criteria, ECGs may be repeated once after 
5 minutes of rest. 
19. Have a family history of Long QT Syndrome. 
20. Have evidence of human immunodeficiency virus (HIV) infection, hepatitis B, hepatitis C 
and/or positive results at screening for the respective antibodies for HIV, hepatitis B surface 
antigen, or hepatitis C antibodies. 
21. Patients who, in the clinician’s judgment, are actively suicidal and therefore deemed to be at 
significant risk for suicide, or those who have answered “yes” to either Question 4 (Active 
Suicidal Ideation with Some Intent to Act, Without Specific Plan) or Question 5 (Active 
Suicidal Ideation with Specific Plan and Intent) on the “Suicidal Ideation” portion of the 
Columbia–Suicide Severity Rating Scale (C-SSRS), or answer “yes” to any of the 
suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt, preparatory 
act or behavior) on the “Suicidal Behavior” portion of the C–SSRS; and the ideation or 
behavior occurred within a month of Visit 1. 
22. Patients on weight loss medications within 30 days of dosing.  Patients with a history of 
bariatric surgery should also be excluded. 
23. Unable to refrain from or anticipates the use of 
a. Any drugs known to be significant inhibitors of cytochrome P450 (CYP)3A 
enzymes and/or P-glycoprotein (P-gp) including regular consumption of 
grapefruit or grapefruit juice for 14 days prior to the first dose of study 
medication and throughout the study.  Appropriate sources will be consulted 


GLWL-PWS(d) Clinical Protocol 
Page 24 
GLWL-01 
by the principal investigator (PI) or designee to confirm lack of PK or 
pharmacodynamic (PD) interaction with study medication.  Acetaminophen 
(up to 2 g per 24-hour period) may be permitted during the study. 
b. Any drugs known to be significant inducers of CYP3A enzymes and/or P-gp, 
including St. John’s Wort, for 28 days prior to the first dose of study 
medication and throughout the study.  Appropriate sources will be consulted 
by the PI or designee to confirm lack of PK/PD interaction with study 
medication. 
c. Any medications that prolong the QT/QTc interval, unless the patient has been 
on a stable dose of said medication for at least 3 months and has a QTc <450 
msec at Visit 1 and Visit 3. 
24. Currently taking simvastatin >10 mg per day, atorvastatin >20 mg per day, or lovastatin 
>20 mg per day.  The doses of these statins in combination products should not exceed these 
defined dose levels.  Patients with a history of statin-induced myopathy/rhabdomyolysis 
should also be excluded. 
25. Current smokers, or any use of tobacco and nicotine products within 3 months of dosing. 
26. Regular user of known drugs of abuse and/or shows positive findings on urinary drug 
screening. 
27. An average weekly alcohol intake that exceeds 21 units per week (males ≤65 years of age) 
and 14 units per week (females and males >65 years of age), or is unwilling to stop alcohol 
consumption for the duration of the study (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL 
of wine; 1.5 oz or 45 mL of distilled spirits). 
28. Venous access insufficient to allow for blood sampling as per the protocol. 
29. Any major surgery within 60 days prior to the first dose or has planned elective surgeries to 
occur during the study. 
30. Unsuitable for inclusion in the study in the opinion of the investigator. 
6.3. Lifestyle Restrictions 
Consumption of foods and beverages containing the following substances will be limited or 
prohibited as indicated: 
• xanthine/caffeine:  throughout the study, patients are required to maintain their regular 
intake of caffeinated beverages for the duration of the study 
• Alcohol:  an average weekly alcohol intake should not exceed 21 units per week (males 
≤65 years of age) and 14 units per week (females and males >65 years of age). 
• Grapefruit/Seville orange:  14 days before first dosing and throughout the study. 
Following the morning dose on Day 14 and Day 42, and on Day 84 and Day 112, patients will 
remain ambulatory or seated upright for the first 4 hours, except when they are supine or 
semi-reclined for study procedures. 
Patients will be instructed to refrain from strenuous physical activity which could cause muscle 
aches or injury, including contact sports at any time from Visit 1 until completion of the study 


GLWL-PWS(d) Clinical Protocol 
Page 25 
GLWL-01 
participation.  Patients should otherwise minimize changes in their activity levels during study 
participation. 
6.4. Screen Failures 
Patients who do not meet the criteria for participation in this study (screen failure) at Visit 1 may 
be rescreened.  Individuals may be rescreened up to 1 time.  The rescreen should be at the 
discretion of the PI after discussion with sponsor medical representative.  If a rescreening is 
performed, the individual must sign a new informed consent form (ICF) and will be assigned a 
new identification number. 


GLWL-PWS(d) Clinical Protocol 
Page 26 
GLWL-01 
7. Treatments 
7.1. Treatments Administered 
GLWL-01 drug product is supplied for clinical trial use as size 0 dark blue opaque capsules for 
oral administration.  Capsules will contain 150 mg of GLWL-01.  No additional excipients are 
used, with the exception of the capsule itself. 
The GLWL-01 drug product placebo will consist of microcrystalline cellulose and magnesium 
stearate filled directly into size 0 dark blue opaque capsules, identical in appearance to 
GLWL-01 150-mg capsules. 
Capsules must be taken whole. 
In Treatment Period 1, all eligible patients will undergo a single-blind (patients/caregiver) 
placebo lead-in phase, wherein they will receive 3 capsules of placebo BID for 14 days.  
Following this, patients will be randomly assigned to either GLWL-01 450 mg BID/placebo or 
placebo/GLWL-01 450 mg BID treatment sequence.  During Treatment Period 1, patients will 
receive 3 capsules of 150-mg GLWL-01 (450-mg total dose) or identical matching placebo BID 
for 28 days.   
Before Treatment Period 2, patients will undergo a 28-day Washout Period following which all 
patients will receive 3 capsules of placebo BID during the 14-day single-blind placebo lead-in 
phase.  
During Treatment Period 2 double-blind treatment phase, patients will receive 3 capsules of 
150-mg GLWL-01 (450-mg total dose) or identical matching placebo BID for 28 days.  The 
double-blind treatment phases in both treatment periods must not exceed 28 days and patients 
must not administer the double-blind study drug beyond 28 days.  The study drugs can be 
administered in fed or fasted conditions. 
The investigator or designee is responsible for 
• explaining the correct use of the study drug to patients and caregivers; 
• verifying that instructions are followed properly; 
• maintaining accurate records of study drug dispensation and collection; 
• and returning all unused medications to sponsor or its designee at the end of the study. 
Note:  In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.  
7.1.1. Packaging and Labeling 
The sponsor or its designee will provide sufficient quantities of GLWL-01 drug products to 
allow completion of this study.  GLWL-01 drug products are manufactured, tested, packaged, 
and labeled in accordance with all applicable good manufacturing practice requirements, 
guidelines, and regulations and will be labeled according to the country’s regulatory 


GLWL-PWS(d) Clinical Protocol 
Page 27 
GLWL-01 
requirements.  A certificate of release confirming that study drugs are released for human use in 
clinical trials will be supplied.  GLWL-01 drug products are for investigational use only and are 
to be used only within the context of this study. 
7.2. Method of Treatment Assignment 
Patients who meet all criteria for enrollment will be randomized 1:1 to 1 of 2 treatment 
sequences:  GLWL-01/placebo or placebo/GLWL-01 (Treatment Period 1 double-blind 
treatment phase/Treatment Period 2 double-blind treatment phase).  Assignment to treatment 
sequence will be determined by a computer-generated random sequence using an interactive 
web-response system (IWRS).  The IWRS will be used to assign bottles containing study drug to 
each patient.  During the patient’s/caregiver’s visit, site personnel will access the IWRS for the 
correct bottle numbers to dispense. 
7.2.1. Timing of Dose Administration 
The doses should be administered at approximately the same times on each day.  
The study drug will be administered at the site on Days 14 and 42 (Treatment Period 1) only. 
7.3. Blinding 
This study has both single-blind (patient and caregiver) and double-blind (patient, caregiver, and 
investigator) phases. 
To preserve the blinding of the study, a minimum number of sponsor personnel will see the 
randomization table and treatment assignments before the study is complete. 
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment.  All calls resulting in an unblinding event are recorded and reported using the IWRS. 
If an investigator, site personnel performing assessments, caregiver, or patient is unblinded, the 
patient must be discontinued from the study.  In cases where there are ethical reasons to retain 
the patient in the study, the investigator must obtain specific approval from the sponsor medical 
representative for the patient to continue in the study. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  The 
patient’s safety must always be the first consideration in making such a determination.  If a 
patient’s treatment assignment is unblinded, the sponsor must be notified immediately.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify the sponsor as soon as possible. 
7.4. Dosage Modification 
Not applicable. 


GLWL-PWS(d) Clinical Protocol 
Page 28 
GLWL-01 
7.5. Preparation/Handling/Storage/Accountability 
The GLWL-01 capsules are supplied in high-density polyethylene bottles.  All GLWL-01 drug 
products will be stored in a secure and locked area with strictly limited access and monitored for 
temperature, and allocated and dispensed by appropriately trained personnel.  Study drugs will 
be stored between 15°C and 30°C. 
The investigator or his/her designee is responsible for the following: 
• confirming appropriate temperature conditions have been maintained during transit for 
all study drugs received and any discrepancies are reported and resolved before use of 
the study drug. 
• ensuring that only participants enrolled in the study may receive study drug and only 
authorized site staff may supply or administer study drug.  All study drugs must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) 
area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff. 
• the investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance (such 
as receipt, reconciliation, and final disposition records). 
7.6. Treatment Compliance 
Patient compliance with study drug will be assessed at the end of each treatment period.  
Compliance will be assessed by counting returned capsules.  The patient will be considered 
significantly noncompliant if he or she takes <80% or >120% of dispensed capsules.  Deviations 
from the prescribed dosage regimen should be recorded in the electronic data capture (EDC). 
7.7. Concomitant Therapy 
Patients may not take any medication (including over-the-counter products), herbal products, or 
vitamin supplements, which are CYP3A and/or P-gp inhibitors for 14 days prior to dosing and 
throughout the study.  In cases that require the use of such medication for the treatment of an AE 
or comorbidity, GLWL-01 dosing must be terminated before the CYP3A inhibitor can be started. 
Medications that prolong the QT/QTc interval are allowed provided the patient has been on a 
stable dose of said medication for at least 3 months and has a QTc < 450 msec at Visit 1 and 
Visit 3.  A list of medications with a potential for QTc prolongation will be provided separately 
to the investigators. 
If the need for the initiation of other medication arises during the study, the investigator must 
consult with sponsor medical representative and such medication change must be reported in the 
EDC. 
All medications taken by patients during the course of the study will be recorded.  Concomitant 
medications will be listed by treatment and coded using the most current World Health 
Organization drug dictionary. 


GLWL-PWS(d) Clinical Protocol 
Page 29 
GLWL-01 
7.8. Treatment after the End of the Study 
Not applicable. 


GLWL-PWS(d) Clinical Protocol 
Page 30 
GLWL-01 
8. Discontinuation Criteria 
Patient participation in the study may be discontinued for any of the following reasons: 
• Enrollment in any other clinical study involving any study drug or enrollment in any 
other type of medical research judged not to be scientifically or medically compatible 
with this study. 
• Investigator’s decision:  the investigator decides that the patient should be discontinued 
from the study. 
• Patient’s/caregiver’s decision:  the patient or caregiver requests to be discontinued 
from the study. 
• Sponsor’s decision:  GLWL stops the study or stops the patient’s participation in the 
study for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and GCP. 
• Adverse event:  any SAE or a significant change in a laboratory value occurs that merits 
the study drug being discontinued and necessitates appropriate measures being taken.  In 
this case, the sponsor is to be notified immediately. 
• Hepatic event or liver test abnormality:  Patients who are discontinued from using 
study drug due to a hepatic event or liver test abnormality should have additional hepatic 
safety data collected via electronic data entry. 
Discontinuation of the study drug for abnormal liver test results should be considered by 
the investigator when a patient meets 1 of the following conditions after consultation 
with the sponsor medical representative: 
o ALT or AST >5X ULN 
o ALT or AST >3X ULN along with 1 of the following criteria: 
 sustained for more than 2 weeks or 
 total bilirubin level (TBL) >2X ULN or 
 prothrombin time >1.5X ULN or 
 the appearance of fatigue, nausea, vomiting, right upper-quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%) 
o ALP >3X ULN 
o ALP >2.5X ULN and TBL >2X ULN 
o ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• Marked prolongation of the QT/QTc interval >500 ms or >60 ms over baseline, judged 
medically significant following repeat ECG after 5 minutes of rest from the initial ECG. 
• A clinically significant systemic hypersensitive reaction occurs following administration 
of the study drug (e.g., study drug-related symptomatic bronchospasm, allergy-related 
edema/angioedema, or hypotension), that requires parenteral medication, does not 
respond to symptomatic medication, or result in clinical sequelae or an anaphylactic 
reaction. 
• An elevated troponin I level (greater than 0.04 ng/mL); the patient must be referred for 
further evaluation. 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
• Patient has stopped eating or drinking for more than 24 hours. 
• Requirement of prohibited concomitant medication. 
• Patient failure to comply with protocol requirements or study-related procedures. 
• Termination of the study by the sponsor or regulatory authorities.  
The clinical report will include reason(s) for patient withdrawals as well as details relevant to the 
patient withdrawal. 
Patient discontinuing from the study prematurely for any reason should complete AE and other 
follow-up procedures per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol. 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site. 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
9. Study Assessments and Procedures 
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing). 
Appendix 2 lists the laboratory tests that will be performed for this study. 
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study. 
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards. 
9.1. Efficacy Assessments 
9.1.1. Primary Efficacy Assessment – Hyperphagia Questionnaire for 
Clinical Trials 
The HQ-CT is a validated tool developed specifically for PWS, to capture observations of 
problematic behaviors related to food.  It was adapted in a rigorous and systematic manner for 
use in clinical trials (HQ for Clinical Trials or HQ-CT) by Zafgen, Inc. for the ZAF-312 clinical 
trial, and donated to the Foundation for Prader-Willi Research in 2016 to facilitate its use across 
clinical trials for PWS.  It consists of 9 items, with a 2-week recall period.  The scale provides a 
composite value from 9 questions, each rated on a scale of zero to 4 units (total range of score of 
zero to 36; Fehnel et al. 2015). 
9.1.2. Secondary Efficacy Assessment – Caregiver Global Impression 
of Change 
Caregiver Global Impression of Change (CGIC) is a single-item question rated on a 0 to 7 scale 
directed at the caregiver asking them to assess overall improvement in patients with PWS.  This 
tool was adapted by Zafgen, Inc. for the ZAF-312 clinical trials. 
9.2. Adverse Events 
A clinical trial AE is any untoward medical event associated with the use of a drug or drug 
delivery system in humans, whether or not it is considered related to that drug or drug delivery 
system. 
The sponsor has standards for reporting AEs that are to be followed regardless of applicable 
regulatory requirements that may be less stringent. 
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting sponsor or its designee to any event that seems unusual, even if this event may 
be considered an unanticipated benefit to the patient. 


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The investigator is responsible for the appropriate medical care of patients during the study. 
Investigators must document their review of each laboratory safety report. 
The investigator remains responsible for following, through an appropriate healthcare option, 
AEs that are serious or otherwise medically important, considered related to the study drug or the 
study, or that caused them to discontinue the study drug before completing the study.  The 
patient should be followed until the event resolves, stabilizes with appropriate diagnostic 
evaluation, or is reasonably explained.  The frequency of follow-up evaluations of the AE is left 
to the discretion of the investigator. 
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect. 
After the ICF is signed, study site personnel will record via EDC the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs.  Investigators should record their assessment of the 
potential relatedness of each AE to protocol procedure or study treatment via EDC.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, or a study procedure, taking into account the disease, 
concomitant treatment, or pathologies.   
A “reasonable possibility” means that there is a cause and effect relationship between the study 
drug, study device, and/or study procedure and the AE. 
The investigator answers yes/no when making this assessment. 
Ratings of AEs will be based on the following 3-point severity scale: 
Mild 
Awareness of sign or symptom, but it is easily tolerated; does not interfere with 
daily activities 
Moderate Discomfort enough to slightly disrupt daily activities.  Medical intervention and/or 
close follow-up may be considered 
Severe 
Incapacitating with complete disruption of daily activities.  Medical intervention 
and/or close follow-up likely. 
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study. 
If a patient’s study drug is discontinued as a result of an AE, study site personnel must report this 
to sponsor or its designee via EDC, clarifying if possible, the circumstances leading to any 
dosage modifications, or discontinuations of treatment. 


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9.2.1. Serious Adverse Events 
Study site personnel must alert the sponsor or its designee of any SAE within 24 hours of 
investigator awareness of the event via a sponsor-approved method.  Serious adverse event 
reporting to the sponsor begins after the patient has signed the ICF. 
If alerts are issued via telephone, they are to be immediately followed with official notification 
on study-specific SAE forms.  This 24-hour notification requirement refers to the initial SAE 
information and all follow-up SAE information.  Patients with a serious hepatic AE should have 
additional data collected using the EDC (Section 9.4.5.1). 
An SAE is any AE from this study that results in 1 of the following outcomes: 
• death 
• initial or prolonged inpatient hospitalization 
• a life-threatening experience (i.e., immediate risk of dying) 
• persistent or significant disability/incapacity 
• congenital anomaly/birth defect 
• important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition above.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.  
 
Previously planned (prior to the signing of ICF) surgeries should not be reported as SAEs unless 
the underlying medical condition has worsened during the course of the study.  
The following terms will be utilized to assess the relationship of the SAE to administration of 
study treatment: 
• Probably related:  a direct cause and effect relationship between the study treatment and 
the AE is likely. 
• Possibly related:  a cause and effect relationship between the study treatment and the AE 
has not been demonstrated at this time and is not probable, but is also not impossible. 
• Unlikely:  likely to be due to another etiology. 
• Not related:  without question, the AE is definitely not associated with the study 
treatment. 
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued and/or completed the study.  Serious adverse events occurring after a patient has 
taken the last dose of study drug will be collected for 30 days after the last dose of the study 
drug.  However, if the investigator learns of any SAE, including a death, at any time after a 
patient has been discharged from the study, and he/she considers the event reasonably possibly 
related to the study treatment or study participation, the investigator must promptly notify the 
sponsor. 


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Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus. 
The medical representative of the sponsor will monitor safety data throughout the course of the 
study.  The sponsor and/or its designee will review SAEs within appropriate timeframes to meet 
reporting obligations imposed by regulatory authorities.  All serious and unexpected AEs for this 
study will be reported to regulatory authorities in accordance with local laws, directives, and 
regulations. 
9.2.1.1. Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB (GLWL-01 2017) and that the investigator identifies as related to the study drug or 
procedure.  The sponsor has procedures that will be followed for identifying, recording, and 
expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidance. 
9.2.2. Complaint Handling 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements. 
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the study drug so that the situation can be assessed. 
9.3. Treatment of Overdose 
Refer to the IB (GLWL-01 2017). 
9.4. Safety 
9.4.1. Electrocardiograms 
For each patient, 12-lead ECG recordings and ECG extractions should be performed according to 
the Schedule of Activities (Section 2). 
Patients must be in a quiet environment without significant external stimulation (e.g., television 
or internet), must be in supine position for at least 5 to 10 minutes before the specified ECG 
collection time, and must remain supine but awake during ECG collection and for at least 
5 minutes afterward.  Patients are to be encouraged to remain still if possible during this time. 
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
patient receives the first dose of the study drug should be reported to the sponsor or its designee 
as an AE via EDC.   


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9.4.2. Vital Signs 
For each patient, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2).  Triplicate measurements (collected approximately 1 minute apart) of 
sitting BP, and single pulse and temperature, will be measured. 
Any clinically significant findings from vital sign measurements that result in a diagnosis and 
that occur after the patient receives the first dose of study drug should be reported to the sponsor 
or its designee as an AE via electronic data entry. 
9.4.3. Laboratory Tests 
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2).  The blood samples should be collected in a fasted state. 
With the exception of laboratory test results that may unblind the study, sponsor or its designee 
will provide the investigator with the results of laboratory tests analyzed by a central vendor, if a 
central vendor is used for the clinical trial. 
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of study drug should be reported to the sponsor or its 
designee as an AE via electronic data entry. 
9.4.4. Columbia Suicide-Severity Rating Scale 
Columbia Suicide-Severity Rating Scale:  A scale that captures the occurrence, severity, and 
frequency of suicidal ideation and/or behavior during the assessment period.  The scale includes 
suggested questions to solicit the type of information needed to determine if suicidal ideation 
and/or behavior occurred.  The C-SSRS is administered by an appropriately trained healthcare 
professional with at least 1 year of patient care/clinical experience or some or all of the patients 
may have these data solicited through interactive web-response system or electronic patient 
reported outcome technology.  This tool was developed by the National Institute of Mental 
Health trial group (Treatment of Adolescent Suicide Attempters) for the purpose of being a 
counterpart to the C-CASA categorization of suicidal events. 
The nonleading AE collection should occur prior to the collection of the C-SSRS.  If a 
suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form.  If an event is serious or leads to 
discontinuation, this is an exception where the SAE and/or AE leading to discontinuation should 
be included on the AE form and the process for reporting SAEs should be followed. 
Terms captured by the use of the C-SSRS can be mapped to Columbia Classification Algorithm 
for Suicide Assessment (Posner et al. 2007) to facilitate future pooling of data. 
The first time the scale is administered in this study, the C-SSRS “Lifetime/Recent-Clinical” 
version will be used, and the findings will constitute the baseline assessment.  The “Since Last 
Visit-Clinical” version will be used for all subsequent assessments.  If a suicide-related thought 
or behavior is identified at any time during the study, a thorough evaluation will be performed by 
a study physician, and appropriate medical care will be provided.  If, based on administration of 


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the C-SSRS, it is determined that suicide-related behaviors have occurred, then the additional 
information will be collected to allow for a more complete assessment of these behaviors. 
9.4.5. Safety Monitoring 
The sponsor and designee will periodically review evolving aggregate safety data within the 
study using appropriate methods. 
9.4.5.1. Hepatic Safety Monitoring 
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X 
ULN, liver tests (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, ALP, 
TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor.  Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to approximate baseline levels.  
Hepatic Safety Data Collection 
Additional safety data should be collected via the electronic data entry if 1 or more of the 
following conditions occur:  
• elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests 
• elevation of serum TBL to ≥2X ULN (except for cases of known Gilbert’s syndrome)  
• elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests 
• patient discontinued from treatment due to a hepatic event or abnormality of liver tests 
• hepatic event considered to be an SAE 
9.5. Pharmacokinetics 
9.5.1. Blood Sampling and Processing 
For all patients, serial blood samples will be collected on Day 1 and Day 28 of Treatment 
Period 1 for the determination of plasma concentrations of GLWL-01.  Sample collection time 
points are specified in the Schedule of Activities (Section 2).  Times of sampling are intended as 
a guide and may be modified to accommodate clinical procedures.  The actual date and time 
(24-hour clock time) of each sample collection will be recorded.  The date and time of dosing on 
the days of PK sample collection will also be recorded.  Instructions for the collection and 
handling of blood samples will be provided by the sponsor in a separate document. 
A maximum of 2 samples may be collected at additional time points during the study if 
warranted and agreed upon between both the investigator and sponsor.  For patients who 
discontinue early, a PK sample should be taken at the early termination visit. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.  Placebo samples are not planned 
to be assayed.  


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9.5.2. Bioanalytical Method 
Plasma sample bioassays of GLWL-01 will be performed using validated procedures and 
methods at a laboratory approved by the sponsor.  Placebo samples will be shipped to the 
laboratory in order to maintain the blind, and are not planned to be assayed. 
Bioanalytical samples collected to measure study drug concentration will be retained for a 
maximum of 1 year following last patient visit for the study. 
9.6. Pharmacodynamics 
9.6.1. Acylated-Ghrelin and Unacylated-Ghrelin 
A separate PD sampling manual will detail the appropriate collection and processing procedures 
to be followed for this study.  For all patients, blood samples for the determination of PD 
assessments (AG and UAG) will be collected at scheduled time points as provided in Schedule 
of Activities (Section 2).  The blood samples should be collected in a fasted state. 
9.7. Biomarkers 
Not applicable.  
9.8. Health Economics 
Not applicable. 


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10. Statistical Considerations 
10.1. Sample Size Determination 
Approximately 34 patients will be randomized to 1 of 2 treatment sequences (GLWL-01/placebo 
or placebo/GLWL-01) in a 1:1 ratio.  Thirty-four patients will provide approximately 80% power 
to detect an effect size of 0.75 for the HQ-CT total score using a 2-sided exact paired t-test with 
an α=0.05, assuming 10% drop out. 
10.2. Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Analysis Set 
Description 
Entered 
All patients who sign informed consent 
Randomized 
All randomized patients who take at least 1 dose of double-blind study drug.  
Patients will be analyzed according to the treatment they actually received. 
10.3. Statistical Analyses 
10.3.1. General Statistical Considerations 
Statistical analysis of this study will be the responsibility of GLWL Research Inc. or its designee. 
Efficacy analyses will be conducted on the randomized analysis set.  This set includes all data 
from all randomized patients receiving at least 1 dose of double-blind study drug.  Patients will 
be included in the analysis if they have a postbaseline measurement for the parameter being 
analyzed.  Safety analyses will be conducted on the randomized analysis set.  Patients will be 
analyzed according to the study drug they actually received. 
Data will be presented using summary tables by treatment, unless otherwise specified. 
Continuous data will be summarized using the mean, standard deviation, median (for selected 
variables), minimum, and maximum.  Categorical data will be summarized as frequency counts 
and percentages.  Figures may be used to support the presentation of selected data. 
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated. 
Baseline values will be defined as the last available value prior to receiving double-blind study 
drug for each double-blind treatment phase. 
For the purposes of follow-up analyses, the first 2 weeks of the washout period will be the 
follow-up for the Treatment Period 1 double-blind treatment phase and the Follow-up Period will 
be the follow-up for the Treatment Period 2 double-blind treatment phase. 
Details related to handling of missing data will be described in the statistical analysis plan (SAP). 
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol.  Any other change to the data analysis 


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GLWL-01 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP and/or in the clinical study report (CSR).   
Additional exploratory analyses of the data will be conducted as deemed appropriate. 
10.3.2. Treatment Group Comparability 
10.3.2.1. Patient Disposition 
All patients who discontinue from the study will be identified, and the extent of their 
participation in the study will be summarized by treatment sequence.  If known, a reason for their 
discontinuation will be given. 
10.3.2.2. Patient Characteristics 
Patient demographics (age, gender, race, ethnicity, height, weight, and BMI) will be summarized 
by treatment sequence for the safety analysis set. 
10.3.2.3. Concomitant Therapy 
Concomitant therapy will be listed. 
10.3.2.4. Treatment Compliance 
Treatment compliance will be calculated for each double-blind treatment phase as 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶= 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 ∗100 
10.3.3. Efficacy Analyses 
10.3.3.1. Primary Analyses 
The primary analysis will be conducted using a restricted maximum likelihood-based, 
mixed-effect model repeated measures analysis.  The analysis of the primary endpoint will be the 
contrast between GLWL-01 and placebo at the end of the double-blind treatment phase on the 
posttreatment HQ-CT score. 
The model for the primary analysis will include the fixed, categorical effects of sequence, period, 
and treatment, as well as the continuous, fixed covariate of the baseline double-blind Treatment 
Period 1 phase HQ-CT score minus the baseline double-blind Treatment Period 2 phase HQ-CT 
score (diff) and the interaction of period*diff (Mehrotra 2014). 
An unstructured covariance structure will be used to model the within-patient errors. 
Sensitivity analyses will be outlined in the SAP. 
10.3.3.2. Secondary Analyses 
The secondary analysis will be conducted similarly to the primary analysis, but the model will 
not include the baseline covariate or interaction.  The secondary efficacy endpoint is the CGIC. 
10.3.3.3. Exploratory Analyses 
The following exploratory endpoints will be analyzed using the same methodology as for the 
primary efficacy analysis: 


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• AG 
• UAG 
• AG/UAG ratio 
• Body weight 
• Percentage fat mass 
• BMI 
• Waist circumference 
• low-density lipoprotein 
• Total cholesterol 
10.3.4. Safety Analyses 
The safety analyses will be conducted for the double-blind treatment phase and follow-up 
combined.  Data will be summarized by treatment group unless otherwise noted.   
The safety and tolerability of treatment will be assessed by evaluating the following: 
• Treatment-emergent adverse events by Preferred Term and maximum severity 
• SAEs 
• AE leading to discontinuation 
• Suicidal ideation and behaviours assessed by solicited questioning using the C-SSRS 
• Vital signs and weight 
• ECGs 
• Laboratory measurements 
Treatment-emergent adverse events are defined as the reported AEs that first occurred or 
worsened during the double-blind treatment phase and follow-up compared with baseline.  The 
most recent version of Medical Dictionary for Regulatory Activities Lowest Level Term (LLT) 
will be used in the treatment-emergent computation.  For each LLT, the maximum severity at 
baseline will be used as the baseline severity.  If the maximum severity during postbaseline is 
greater than the maximum baseline severity, the event is considered to be treatment emergent for 
the specific postbaseline period.  Treatment-emergent adverse events will be summarized by the 
number and percentage of patients with the event. 
For events that are gender-specific, the denominator and computation of the percentage will 
include only patients from the given gender. 
Suicidal ideation, suicidal behavior, and nonsuicidal self-injurious behavior based on the 
C-SSRS will be listed. 
Vital signs collected during the study include systolic and diastolic BP, pulse, and temperature.  
Blood pressure and pulse measurements will be taken when the patient is in a sitting position.  
Three measurements of sitting BP will be collected at approximately 30- to 60-sec intervals and 
those 3 sitting BP will be averaged and used as the value for that visit for analysis. 


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The incidence rates of patients with clinically significant vital sign and weight changes at any 
time postbaseline will be assessed using Fisher’s exact test.  The clinically significant criteria 
will be documented in the SAP. 
The QT and QTcF interval will be summarized with the number and percentage of patients with 
values >450 msec, >480 msec, and >500 msec at any time postbaseline. 
The incidence rates of patients with treatment-emergent abnormal, high, or low laboratory values 
at any time postbaseline will be assessed using Fisher’s exact test for each laboratory test.  
Patients will be defined as having a treatment-emergent low value if they have all normal or high 
values at baseline, followed by a value below the lower reference limit at any postbaseline visit.  
Patients with all normal or high values at baseline (no low values) will be included in the 
analysis of treatment-emergent low laboratory values.  Patients will be defined as having a 
treatment-emergent high value if they have all normal or low values at baseline, followed by a 
value above the upper reference limit at any postbaseline visit.  Patients with all normal or low 
values at baseline (no high values) will be included in the analysis of treatment-emergent high 
laboratory values. 
For analytes simply classified as normal or abnormal, patients will be defined as having a 
treatment-emergent abnormal value if they have all normal values at baseline, followed by an 
abnormal value at any postbaseline visit.  Patients with all normal values at baseline will be 
included in the analysis of treatment-emergent abnormal laboratory values.  
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses 
Plasma GLWL-01 PK parameters will be calculated using noncompartmental methods after 
single and multiple dose administration (on Day 1 and Day 28 of Treatment Period 1, 
respectively).  Additional PK parameters may be calculated if deemed appropriate. 
Pharmacokinetic parameters will be summarized by dose level using descriptive statistics.  Mean 
and individual GLWL-01 plasma concentration-time curves will be represented graphically. 
Accumulation will be estimated.  Additional analyses will be performed as deemed necessary 
upon review of the data. 
Pharmacokinetic data may be fit with a population PK model; and may be pooled with data from 
previous studies.  
Pharmacodynamics of GLWL-01 will be based on plasma AG and potentially UAG measures.  
Raw and change from baseline values will be reported and summarized for AG and potentially 
UAG. 
The PK/PD relationship of GLWL-01 with PD, efficacy, and/or safety measures may be 
explored. 
10.3.6. Evaluation of Immunogenicity 
Not applicable. 


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GLWL-01 
10.3.7. Interim Analyses 
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate sponsor medical representative will be consulted to determine whether 
it is necessary to amend the protocol. 


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11. References 
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Callaghan B, Furness JB. Novel and conventional receptors for ghrelin, desacyl-ghrelin, and 
pharmacologically related compounds. Pharmacol Rev. 2014;66(4):984-1001. 
Chen CY, Asakawa A, Fujimiya M, Lee SD, Inui A. Ghrelin gene products and the regulation of 
food intake and gut motility. Pharmacol Rev. 2009;61(4):430-481. 
Cummings DE, Frayo RS, Mormonier C, Aubert R, Chapelot D. Plasma ghrelin levels and 
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Physiol Endocrinol Metab. 2004;287(2):E297-E304. 
FDA 2012 Guidance for Industry and Investigator: Safety Reporting Requirements for INDs and 
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Fehnel S, Brown TM, Nelson L, Chen A, Roof E, Kim DD, Dykens EM. Development of the 
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[GLWL-01] GLWL Research Inc. July 2017. Investigator’s Brochure for GLWL-01. 
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Trends Endocrinol Metab. 2004;15(1):12-20. 
Kuppens RJ, Diene G, Bakker NE, Molinas C, Faye S, Nicolino M, Bernoux D, Delhanty PJ, van 
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Kweh FA, Miller JL, Sulsona CR, Wasserfall C, Atkinson M, Shuster JJ, Goldstone AP, Driscoll 
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Mehrotra D. A recommended analysis for 2 × 2 crossover trials with baseline measurements. 
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Posner K, Oquendo MA, Gould M, Stanley B, Davies M.  Columbia Classification Algorithm of 
Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal 
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Purtell L, Sze L, Loughnan G, Smith E, Herzog H, Sainsbury A, et al. In adults with Prader-Willi 
syndrome, elevated ghrelin levels are more consistent with hyperphagia than high PYY and 
GLP-1 levels. Neuropeptides. 2011;45(4):301-307. 
PWSA USA Resource Page 1. Prader-Willi Syndrome Association USA web site. Available at: 
http://www.pwsausa.org/basic-facts/. Accessed June 08, 2017. 


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PWSA USA Resource Page 2. Medical overview: a diagnosis and reference guide for physicians 
and other health professionals for treatment of individual with Prader-Willi syndrome. 
Available at: http://pwsausa.org/wp-content/uploads/2015/11/Medical-Overview-for-
Professionals-MA-GA-02-020613.pdf. Accessed June 08, 2017. 
The University of Chicago Resource Page.  Pediatric Clerkship: Prader-Willi syndrome.  
Availbale at: https://pedclerk.bsd.uchicago.edu/page/prader-willi-syndrome. Accessed on 
June 08, 2017.  
Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 
2000;407(6806):908-913. 
Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, 
Bloom SR. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol 
Metab. 2001a;86(12):5992-5995. 
Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal LJ, Cohen MA, Batterham RL, Taheri S, 
Stanley SA, Ghatei MA, Bloom SR. Ghrelin causes hyperphagia and obesity in rats. Diabetes. 
2001b;50(11):2540-2547.  


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
12. Appendices 


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Appendix 1. 
Abbreviations and Definitions 
Term 
Definition 
AE 
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
AG 
acylated-ghrelin 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BID 
twice a day 
blinding 
A double-blind study is one in which neither the patient/caregiver nor any of the 
investigator or sponsor staff who are involved in the treatment or clinical evaluation of 
the patients are aware of the treatment received. 
BMI 
body mass index 
BP 
blood pressure 
CGIC 
Caregiver Global Impression of Change 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CSR 
clinical study report 
C-SSRS 
Columbia–Suicide Severity Rating Scale 
CYP 
cytochrome P450 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
enroll 
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment. 


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GLWL-01 
enter 
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives. 
ERB 
ethical review board 
FSH 
follicle-stimulating hormone 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
GHSR-1a 
growth hormone secretagogue receptor 
GOAT 
ghrelin-O-acyltransferase 
HIV 
human immunodeficiency virus 
HQ-CT 
Hyperphagia Questionnaire for Clinical Trials 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
informed consent 
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the patient’s decision to participate.  Informed consent is documented by 
means of a written, signed, and dated informed consent form. 
IWRS 
interactive web-response system 
LLT 
Lowest Level Term 
P-gp 
P-glycoprotein 
PI 
principal investigator 
PK/PD 
pharmacokinetic(s)/pharmacodynamics 
PWS 
Prader-Willi syndrome 
QD 
once daily 
QTcF 
corrected QT interval with Frederica’s correction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
screen 
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  


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GLWL-01 
study drug 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
SUSAR 
suspected unexpected serious adverse reaction 
TBL 
total bilirubin level 
TEAE 
treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment. 
UAG 
unacylated-ghrelin 
ULN 
upper limit of normal 


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GLWL-01 
Appendix 2. 
Clinical Laboratory Tests 
Hematologya,b 
Clinical Chemistrya 
Hemoglobin 
Serum Concentrations of: 
Hematocrit 
Sodium 
Erythrocyte count (red blood cell [RBC]) 
Potassium 
Mean cell volume 
Bicarbonate 
Mean cell hemoglobin concentration 
Chloride 
Leukocytes (white blood cell [WBC]) 
Calcium 
Cell morphology 
Phosphorus  
Absolute/relative/% counts of 
Magnesium 
Neutrophils 
Glucose (fasting)  
Lymphocytes 
Blood urea nitrogen (BUN) 
Monocytes 
Total cholesterol 
Eosinophils 
Total protein 
Basophils 
Albumin  
Platelets 
Total bilirubin  
Creatinine 
Estimated glomerular filtration rate (eGFR)d 
 
Urinalysisa 
Alkaline phosphatase (ALP) 
Specific gravity 
Aspartate aminotransferase (AST) 
pH 
Alanine aminotransferase (ALT) 
Protein 
 
Glucose 
Gamma-glutamyl transferase (GGT) 
Ketones 
 
Bilirubin 
Troponin I 
Urobilinogen 
 
Blood 
Additional tests 
Nitrite 
High-density lipoprotein cholesterol (HDL-c) 
Creatinine 
Triglycerides (TG) 
Ethanol testingb,c 
Calculated low-density lipoprotein cholesterol (LDL-c) 
Urine drug screenb,c 
 
Hepatitis B surface antigenb 
 
Hepatitis C antibodyb 
 
Human immunodeficiency virus (HIV)b 
 
Pregnancy test (serum, in females only) 
 
Serum follicle-stimulating hormone (FSH; in 
postmenopausal females only) 
 
Thyroid-stimulating hormone 
 
a Results will be reported and/or validated by the Central Laboratory at the time of initial testing.  If urinalysis is 
positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic examination (for RBCs, WBCs, bacteria, 
casts, and epithelial cells) will be performed. 
b Performed at screening only.  
c Urine drug screen and ethanol level may be repeated as needed. 
d eGFR will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 
(utilizing enzymatic creatinine). 


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Appendix 3. 
Study Governance Considerations 
Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Appendix 3.1.1. 
Informed Consent 
The investigator is responsible for 
• ensuring that the patients understand the nature of the study, the potential risks and 
benefits of participating in the study, and that their participation is voluntary. 
• ensuring that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of study drug. 
• answering any questions the patient may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the patient’s willingness to 
continue his or her participation in the study. 
• ensuring that a copy of the ICF is provided to the participant or the participant’s legal 
representative and is kept on file. 
• ensuring that the medical record includes a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written consent 
was obtained.  The authorized person obtaining the informed consent must also sign the 
ICF. 
Appendix 3.1.2. 
Recruitment 
The sponsor or designee is responsible for the central recruitment strategy for patients.  
Individual investigators may have additional local requirements or processes. 
Appendix 3.1.3. 
Ethical Review 
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International Council 
for Harmonisation (ICH) guidelines and other applicable laws and regulations. 
Documentation of ERB approval of the protocol and the ICF must be provided to the sponsor 
before the study may begin at the investigative sites.  The sponsor or its representatives must 
approve the ICF, including any changes made by the ERBs, before it is used at the investigative 
site(s).  All ICFs must be compliant with the ICH guideline on GCP. 
The study site’s ERB(s) should be provided with the following: 
• the protocol and related amendments and addenda, current IB and updates during the 
course of the study 
• ICF 
• other relevant documents (e.g., curricula vitae, advertisements) 


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Appendix 3.1.4. 
Regulatory Considerations 
This study will be conducted in accordance with the protocol and with the 
• consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
• applicable ICH GCP Guidelines 
• applicable laws and regulations 
Some of the obligations of the sponsor will be assigned to a third party. 
Appendix 3.1.5. 
Investigator Information 
Licensed physicians with a specialty in endocrinology or internal medicine will participate as 
investigators in this clinical trial. 
Appendix 3.1.6. 
Protocol Signatures 
The sponsor’s medical representative will approve the protocol, confirming that, to the best of 
his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study. 
After reading the protocol, each PI will sign the protocol signature page and send a copy of the 
signed page to the sponsor representative. 
Appendix 3.1.7. 
Final Report Signature 
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.  The investigator with the most analyzable patients will serve as the CSR 
coordinating investigator.  If this investigator is unable to fulfill this function, another 
investigator will be chosen by the sponsor to serve as the CSR coordinating investigator. 
The sponsor’s medical representative and statistician will approve the final CSR for this study, 
confirming that, to the best of his or her knowledge, the report accurately describes the conduct 
and results of the study. 
Appendix 3.2. 
Data Quality Assurance 
To ensure accurate, complete, and reliable data, sponsor or its representatives will do the 
following: 
• provide instructional material to the study sites, as appropriate 
• sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the EDCs, and 
study procedures. 
• make periodic visits to the study site 


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GLWL-01 
• be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax 
• review and evaluate EDC data and use standard computer edits to detect errors in 
data collection 
• conduct a quality review of the database 
In addition, sponsor or its designee will periodically check a sample of the patient data recorded 
against source documents at the study site.  The study may be audited by sponsor or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs. 
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents. 
Appendix 3.2.1. 
Data Capture System 
An EDC system will be used in this study.  The site maintains a separate source for the data 
entered by the site into the sponsor-provided EDC system. 
Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data or ECG data, will be stored electronically in the 
central vendor’s database system.  Data will subsequently be transferred from the central vendor 
to the sponsor.  
Appendix 3.3. 
Study and Site Closure 
Appendix 3.3.1. 
Discontinuation of Study Sites 
Study site participation may be discontinued if sponsor or its designee, the investigator, or the 
ERB of the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and GCP. 
Appendix 3.3.2. 
Discontinuation of the Study 
The study will be discontinued if sponsor or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP. 


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Appendix 4. 
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality 
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician. 
Hepatic Monitoring Tests 
Hepatic Hematologya 
Haptoglobina 
Hemoglobin 
 
Hematocrit 
Hepatic Coagulationa 
RBC 
Prothrombin time 
WBC 
Prothrombin time, INR 
Neutrophils, segmented 
 
Lymphocytes 
Hepatic Serologiesa,b 
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Hepatitis B surface antigen 
Platelets 
Hepatitis B surface antibody 
 
Hepatitis B core antibody 
Hepatic Chemistrya 
Hepatitis C antibody 
Total bilirubin 
Hepatitis E antibody, IgG 
Direct bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
 
ALT 
Anti-nuclear Antibody 
AST 
 
GGT 
Alkaline Phosphatase Isoenzymesa 
CPK 
 
 
 
Anti-smooth Muscle Antibody (or Anti-actin 
Antibody)a 
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; 
RBC = red blood cell; WBC = white blood cell. 
a Assayed by sponsor-designated or local laboratory. 
b Reflex/confirmation dependent on regulatory requirements and/or testing availability. 
 


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GLWL-01 
Appendix 5. 
Sampling Summary 
This table summarizes the approximate number of samples and volumes for all sampling and 
tests during the study.  Fewer samples may actually be taken, but this will not require a protocol 
amendment. 
Protocol GLWL-PWS Sampling Summary 
 
Purpose 
Sample 
Type 
Maximum Amount 
per Sample 
Maximum 
Number of 
Samples 
Maximum 
Total Amount 
Screening testsa 
Blood 
21 mL 
1 
21 mL 
Standard laboratory testsa 
Blood 
2 mL 
5 
10 mL 
Drug concentration 
Blood 
2 mL 
14 
28 mL 
AG and UAG samples 
Blood 
4 mL 
5 
20 mL 
On-study serum chemistry 
(includes serum thyroid-
stimulating hormone, lipid 
panel, troponin, and serum 
pregnancy when done at the 
same time) 
Blood 
15 mL 
5 
75.0 mL 
Total 
Blood 
- 
- 
154.0 mL 
Hepatic monitoringb 
Blood 
3 - 30 mL 
- 
- 
a Additional samples may be drawn if needed for safety purposes. 
b Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with Lilly-designated Medical Monitor. 
 
 


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GLWL-01 
Appendix 6. 
Protocol Amendment GLWL-PWS(a) 
Summary [A Phase 2 Study to Evaluate Efficacy, Safety, 
and Pharmacokinetics of GLWL-01 in the Treatment of 
Patients with Prader-Willi Syndrome] 
Overview 
Protocol GLWL-PWS [A Phase 2 Study to Evaluate Efficacy, Safety, and Pharmacokinetics of 
GLWL-01 in the Treatment of Patients with Prader-Willi Syndrome] has been amended.  The 
new protocol is indicated by amendment (a) and will be used to conduct the study in place of any 
preceding version of the protocol. 
The overall changes and rationale for the changes made to this protocol are as follows: 
• Serum pregnancy test has been added at the end of the second Double Blind Treatment 
Phase [Visit 10 (day 112)] and Early Termination Visit for women of childbearing 
potential, per requested change by Health Canada. 
• Exclusion criteria for family history of Long QT Syndrome, now Exclusion Criteria #19 
has been added, per requested change by Health Canada . 
• Now Exclusion Criteria #23(c), the use of any medications that prolong the QT/QTc 
interval is excluded, per requested change by Health Canada. 
• In Section 7.7 Concomitant Medications, consistency sentences were added to indicate 
that medications that prolong the QT/QTc interval are prohibited and that a list will be 
provided separately and updated as data evolves, per request by Health Canada. 
• In Section 8 Discontinuation Criteria, marked prolongation of the QT/QTc interval >500 
ms or >60 ms over baseline, judged medically significant following repeat ECG after 5 
minutes of rest from the initial ECG was added, per request by Health Canada. 
• Minor textual edits were made for the purpose of clarification or correction. 
 
 


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GLWL-01 
Revised Protocol Sections 
Note: 
Deletions have been identified by strikethroughs or grayed out for figures. 
Additions have been identified by the use of underscore. 
 


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GLWL-01 
2.  Schedule of Activities 
 


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GLWL-01 
Table GLWL-PWS.3. Schedule of Activities 
Period 
Screeninga 
Treatment Period 1 
Washout 
(28 days) 
Treatment Period 2 
Follow-up 
ETc 
Phase 
 
Single-blind 
Placebo 
Lead-in 
Phase 
(14 days) 
Double-blind 
Treatment Phase 
(28 days)b 
 
Single-blind 
Placebo 
Lead-in 
(14 days) 
Double-blind 
Treatment Phase 
(28 days)b 
 
Visit No/ 
Type Procedure 
V1 
 
V2d 
Caregiver 
V3e 
 
V4f 
Phone 
V5 
 
V6  
Phone 
V7d 
Caregiver 
V8 
 
V9f 
Phone 
V10 
 
V11 
 
Day  
-28 to -3 
1 
(±3) 
14 
(±2) 
28 
(±2) 
42 
(±2) 
56 
(±2) 
70 
(±2) 
84 
(±2) 
98 
(±2) 
112 
(±2) 
126  
(±3) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationg 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Heighth 
X 
 
 
 
 
 
 
 
 
 
 
 
Initial history/ preexisting conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAg, HCAB, HIV  
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisi 
X 
 
 
 
 
 
 
 
 
 
 
 
Substance abuse screenj 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion review 
X 
 
Xe 
 
 
 
 
 
 
 
 
 
Study drug dispensing 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
Study drug administration at site 
 
 
X 
 
X 
 
 
 
 
 
 
 
Study drug accountability 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
Efficacy and Outcome Measures 
HQ-CT 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGIC 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Body weighth 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Percentage fat mass (calipers) 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
BMI 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Waist circumference 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Vital signsk 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
Period 
Screeninga 
Treatment Period 1 
Washout 
(28 days) 
Treatment Period 2 
Follow-up 
ETc 
Phase 
 
Single-blind 
Placebo 
Lead-in 
Phase 
(14 days) 
Double-blind 
Treatment Phase 
(28 days)b 
 
Single-blind 
Placebo 
Lead-in 
(14 days) 
Double-blind 
Treatment Phase 
(28 days)b 
 
Visit No/ 
Type Procedure 
V1 
 
V2d 
Caregiver 
V3e 
 
V4f 
Phone 
V5 
 
V6  
Phone 
V7d 
Caregiver 
V8 
 
V9f 
Phone 
V10 
 
V11 
 
Day  
-28 to -3 
1 
(±3) 
14 
(±2) 
28 
(±2) 
42 
(±2) 
56 
(±2) 
70 
(±2) 
84 
(±2) 
98 
(±2) 
112 
(±2) 
126  
(±3) 
12-lead ECGl 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Serum pregnancy testm 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Urine pregnancy testm 
 
 
X 
 
 
 
 
X 
 
 
 
 
Clinical chemistry and hematologyi 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Lipid panel 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
AG and UAGn 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Plasma sample collection for PK 
analysiso 
 
 
X 
 
X 
 
 
 
 
 
 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations:  AE = adverse event; AG = acylated-ghrelin; BMI = body mass index; CGIC = Caregiver Global Impression of Change; C-SSRS = Columbia–Suicide Severity 
Rating Scale; ECG = electrocardiogram; EDC = electronic data capture; ET = early termination; HQ-CT = Hyperphagia Questionnaire for Clinical Trials; HBsAg = hepatitis B 
surface antigen; HCAB = hepatitis C antibody; HIV = human immunodeficiency virus; PK = pharmacokinetic; UAG = unacylated-ghrelin; V = Visit. 
a 
Screening visit must occur between -28 days to -3 days of V2. 
b 
Double-blind Treatment Phase must not exceed 28 days and patients must not take the study drug beyond 28 days.  For example, if the V3 occurs on Day 14, then 
corresponding V5 would occur on Day 42.  Similarly, if V3 occurs on Day 15 (Day 14 +1), then corresponding V5 would occur on Day 43 (Day 42 +1).  
c 
The primary reason for early termination of the patient will be entered in EDC and recorded in the patient’s source documents.  The patient will attend an early termination visit 
as soon as possible after participation ceases. 
d 
Caregiver only visit; patient does not need to attend in person. 
e 
Confirm that the patient has met all inclusion/exclusion criteria.  Patients will only be dosed after the investigator has completed the appropriate protocol assessments and 
determined that it is acceptable to dose the patient. 
f 
Patients/caregivers will receive phone calls from the site; no visit required. 
g 
A full physical examination with neurological assessments should be performed at Visit 1.  Symptom-driven physical examinations should be performed at V3, V5, and V8, 
V10,V11, and at ET.  


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
h 
Height will only be measured at Visit 1.  Patients should be instructed to wear lightweight clothing and remove shoes during weighing.   
i 
Refer to Appendix 2 for details on serum chemistry, hematology, and urinalysis clinical laboratory tests. 
j 
Substance abuse screen test to be performed at Visit 1 and additionally at any visit per investigator’s discretion. 
 
k 
Vital sign assessments will include triplicate sitting blood pressure, and single pulse and body temperature.  Additional vital sign assessments may be performed as clinically 
indicated.  For visits in which both vital signs and blood samples are collected, vital signs should be obtained prior to blood collection.  Any clinically significant result of vital 
sign assessment will be documented in the source documentation and EDC as an AE. 
l 
Single 12-lead ECGs to be collected according to the schedule and may be collected at any time if deemed clinically necessary.  Patients must be supine for at least 5 minutes 
prior to ECG collection.  When ECG collections are scheduled at the same time point as any other tests, ECGs, followed by vital signs, should be recorded prior to any clinical 
laboratory or PK blood sampling. 
m For all female patients, the investigator will document potential childbearing status.  For women who are postmenopausal, a confirmatory test of serum follicule-stimulating 
hormone and estradiol levels will be done at Visit 1.  For all women of childbearing potential, a pregnancy serum test will be done at Visit 1, which must be negative to enroll.  
Subsequently, urine pregnancy tests will be done for all women of childbearing potential as indicated in the schedule; the results must be confirmed negative.  In case of a 
positive urine pregnancy test, the serum pregnancy test must be performed to confirm the pregnancy results. 
n 
The blood samples for AG and UAG should be collected in the fasted state. 
o 
On Day 14 and Day 42, a total of 7 PK samples each day will be taken at the following times:  pre-dose, and 0.5, 1, 2, 4, 6, and between 8 and 12 hours postdose.  Times of 
sampling are intended as a guide and can be modified to accommodate clinical procedures.  Actual time of sample must be collected, as well as date and time of dosing on the 
day of PK sample collection.  For patients who discontinue early, a sample should be obtained at the ET visit.  
 
 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
6.2 
Exclusion Criteria 
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening: 
9. Are Eli Lilly and Company, GLWL Research Inc. (sponsor hereafter), contract research 
organization employees, investigator or site personnel directly affiliated with this study and 
their immediate families.  Immediate family is defined as a spouse, parent, child or sibling, 
whether biological or legally adopted. 
10. Are currently enrolled in any other clinical trial involving a study drug or off-label use of a 
drug or device, or any other type of medical research judged not to be scientifically or 
medically compatible with this study.  
11. Participated in a clinical trial within 30 days (defined as last dose of study drug), prior to the 
GLWL-PWS first dose.  
12. Are currently living in a group home for more than 50% of the time. 
13. Have a HQ-CT total score at Visit 3 <13. 
14. Have clinical laboratory test results outside normal reference range, or any clinically 
significant laboratory abnormality, that in the judgment of the investigator, indicates a 
medical problem that would preclude study participation.  Values for aspartate 
aminotransferase (AST)/alanine aminotransferase (ALT)/gamma-glutamyl transferase 
(GGT)/alkaline phosphatase (ALP) >3X upper limit of normal (ULN). 
15. Have an estimated glomerular filtration rate <60 mL/minute/1.73 m2.  Have 
macroalbuminuria (defined as spot urine albumin to creatinine ratio of >300 µg/mg) or 
hematuria. 
16. Are hypertensive (defined as sitting systolic BP ≥140 mmHg and diastolic BP ≥90 mmHg) 
on or off medications for the treatment of hypertension.  Blood pressure may be re-tested up 
to 2 additional times, under well-rested conditions. 
17. In addition to conditions described below, have a history or presence of any other medical 
illness including but not limited to any autoimmune disorder, cardiovascular, hepatic, 
respiratory, hematological, or uncontrolled neurological disease. 
a) Have a history of clinically overt uncontrolled or untreated endocrine illness such as 
growth hormone insufficiency, adrenal gland, or thyroid illness. 
b) Have evidence of other chronic liver disease, including but not limited to chronic 
alcoholic disease, cirrhosis of any cause, recent history (within 3 months of screening) 
of acute viral hepatitis or chronic autoimmune hepatitis.  Patients with a history of 
biliary disease, including primary sclerosing cholangitis, must be excluded.  Patients 
with a history of cholecystectomy longer than 6 months prior to screening could be 
enrolled. 
c) Have evidence of significant active or unstable/uncontrolled psychiatric disease by 
medical history, such as bipolar disorder, schizophrenia, personality disorders, or other 
serious mood or anxiety disorders.  Note:  Patients whose disease state is considered 
stable and expected to remain stable throughout the course of the study, in the opinion of 
the investigator, may be considered for inclusion if they are not on excluded 
medications. 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
18. Have an abnormality in the 12-lead electrocardiogram (ECG), including corrected QT 
interval with Frederica’s correction (QTcF) >450 msec for men and >470 msec for women 
or an abnormality that, in the opinion of the investigator, increases the risks associated with 
participating in the study.  If QTcF does not meet criteria, ECGs may be repeated once after 
5 minutes of rest. 
19. Have a family history of Long QT Syndrome. 
20. Have evidence of human immunodeficiency virus (HIV) infection, hepatitis B, hepatitis C 
and/or positive results at screening for the respective antibodies for HIV, hepatitis B surface 
antigen, or hepatitis C antibodies. 
21. Patients who, in the clinician’s judgment, are actively suicidal and therefore deemed to be at 
significant risk for suicide, or those who have answered “yes” to either Question 4 (Active 
Suicidal Ideation with Some Intent to Act, Without Specific Plan) or Question 5 (Active 
Suicidal Ideation with Specific Plan and Intent) on the “Suicidal Ideation” portion of the 
Columbia–Suicide Severity Rating Scale (C-SSRS), or answer “yes” to any of the 
suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt, preparatory 
act or behavior) on the “Suicidal Behavior” portion of the C–SSRS; and the ideation or 
behavior occurred within a month of Visit 1. 
22. Patients on weight loss medications within 30 days of dosing.  Patients with a history of 
bariatric surgery should also be excluded. 
23. Unable to refrain from or anticipates the use of 
a) Any drugs known to be significant inhibitors of cytochrome P450 (CYP)3A enzymes 
and/or P-glycoprotein (P-gp) including regular consumption of grapefruit or grapefruit 
juice for 14 days prior to the first dose of study medication and throughout the study.  
Appropriate sources will be consulted by the principal investigator (PI) or designee to 
confirm lack of PK or pharmacodynamic (PD) interaction with study medication.  
Acetaminophen (up to 2 g per 24-hour period) may be permitted during the study. 
b) Any drugs known to be significant inducers of CYP3A enzymes and/or P-gp, including 
St. John’s Wort, for 28 days prior to the first dose of study medication and throughout 
the study.  Appropriate sources will be consulted by the PI or designee to confirm lack 
of PK/PD interaction with study medication. 
c) Any medications that prolong the QT/QTc interval. 
24. Currently taking simvastatin >10 mg per day, atorvastatin >20 mg per day, or lovastatin 
>20 mg per day.  The doses of these statins in combination products should not exceed these 
defined dose levels.  Patients with a history of statin-induced myopathy/rhabdomyolysis 
should also be excluded. 
25. Current smokers, or any use of tobacco and nicotine products within 3 months of dosing. 
26. Regular user of known drugs of abuse and/or shows positive findings on urinary drug 
screening. 
27. An average weekly alcohol intake that exceeds 21 units per week (males ≤65 years of age) 
and 14 units per week (females and males >65 years of age), or is unwilling to stop alcohol 
consumption for the duration of the study (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL 
of wine; 1.5 oz or 45 mL of distilled spirits). 
28. Venous access insufficient to allow for blood sampling as per the protocol. 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
29. Any major surgery within 60 days prior to the first dose or has planned elective surgeries to 
occur during the study. 
30. Unsuitable for inclusion in the study in the opinion of the investigator. 
7.7 
Concomitant Therapy 
Patients may not take any medication (including over-the-counter products), herbal products, or 
vitamin supplements, which are CYP3A and/or P-gp inhibitors for 14 days prior to dosing and 
throughout the study.  In cases that require the use of such medication for the treatment of an AE 
or comorbidity, GLWL-01 dosing must be terminated before the CYP3A inhibitor can be started. 
Medications that prolong the QT/QTc interval are prohibited.  A list will be provided separately 
and updated as data evolves. 
If the need for the initiation of other medication arise during the study, the investigator must 
consult with sponsor medical representative and such medication change must be reported in the 
EDC. 
All medications taken by patients during the course of the study will be recorded.  Concomitant 
medications will be listed by treatment and coded using the most current World Health 
Organization drug dictionary. 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
8. Discontinuation Criteria 
Patient participation in the study may be discontinued for any of the following reasons: 
• Enrolment in any other clinical study involving an study drug or enrolment in any other 
type of medical research judged not to be scientifically or medically compatible with this 
study. 
• Investigator’s decision:  the investigator decides that the patient should be discontinued 
from the study. 
• Patient’s/caregiver’s decision:  the patient or caregiver requests to be discontinued 
from the study. 
• Sponsor’s decision:  GLWL stops the study or stops the patient’s participation in the 
study for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and GCP. 
• Adverse event:  any SAE or a significant change in a laboratory value occurs that merits 
the study drug being discontinued and necessitates appropriate measures being taken.  In 
this case, the sponsor is to be notified immediately. 
• Hepatic event or liver test abnormality:  Patients who are discontinued from using 
study drug due to a hepatic event or liver test abnormality should have additional hepatic 
safety data collected via electronic data entry. 
Discontinuation of the study drug for abnormal liver test results should be considered by 
the investigator when a patient meets 1 of the following conditions after consultation 
with the sponsor medical representative: 
o ALT or AST >5X ULN 
o ALT or AST >3X ULN along with 1 of the following criteria: 
 sustained for more than 2 weeks or 
 total bilirubin level (TBL) >2X ULN or 
 prothrombin time >1.5X ULN or 
 the appearance of fatigue, nausea, vomiting, right upper-quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%) 
o ALP >3X ULN 
o ALP >2.5X ULN and TBL >2X ULN 
o ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• Marked prolongation of the QT/QTc interval >500 ms or >60 ms over baseline, judged 
medically significant following repeat ECG after 5 minutes of rest from the initial ECG. 
• A clinically significant systemic hypersensitive reaction occurs following administration 
of the study drug (e.g., study drug-related symptomatic bronchospasm, allergy-related 
edema/angioedema, or hypotension), that requires parenteral medication, does not 
respond to symptomatic medication, or result in clinical sequelae or an anaphylactic 
reaction. 
• Requirement of prohibited concomitant medication. 
• Patient failure to comply with protocol requirements or study-related procedures. 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
• Termination of the study by the sponsor or regulatory authorities.  
The clinical report will include reason(s) for patient withdrawals as well as details relevant to the 
patient withdrawal. 
Patient discontinuing from the study prematurely for any reason should complete AE and other 
follow-up procedures per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol. 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site. 
 
 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
Appendix 7. 
Protocol Amendment GLWL-PWS(b) 
Summary [A Phase 2 Study to Evaluate Efficacy, Safety, 
and Pharmacokinetics of GLWL-01 in the Treatment of 
Patients with Prader-Willi Syndrome] 
Overview 
Protocol GLWL-PWS [A Phase 2 Study to Evaluate Efficacy, Safety, and Pharmacokinetics of 
GLWL-01 in the Treatment of Patients with Prader-Willi Syndrome] has been amended.  The 
new protocol is indicated by amendment (b) and will be used to conduct the study in place of any 
preceding version of the protocol. 
The overall changes and rationale for the changes made to this protocol are as follows: 
• Troponin I testing has been added to Visits 3, 4, 5, 8, 9, and 10 as requested by FDA 
• ECGs 2 hours post-dose have been added at Visits 3 and 8 as requested by FDA 
• ECGs have been added to Visits 4 and 9 as requested by FDA 
• Visit 4 occurs on Day 21 and visit 9 occurs on Day 91 as requested by FDA 
• Visits 2 and 7 will be phone visits due to change of Visits 4 and 9 to in-person visits 
• The following discontinuation criteria have been added as requested by FDA: 
o Patients with elevated troponin I level (greater than 0.04 ng/mL) must be 
withdrawn from the study.  Elevations must be referred for further evaluation. 
o Patients who have stopped eating or drinking for more than 24 hours must be 
withdrawn from the study. 
• Minor textual edits were made for the purpose of clarification or correction. 
 
 


GLWL-PWS(d) Clinical Protocol 
Page 68 
GLWL-01 
Revised Protocol Sections 
Note: 
Deletions have been identified by strikethroughs or grayed out for figures. 
Additions have been identified by the use of underscore. 
 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
1. Synopsis 
Title of Study: 
A Phase 2 Study to Evaluate Efficacy, Safety, and Pharmacokinetics of GLWL-01 in the 
Treatment of Patients with Prader-Willi Syndrome (PWS)  
Rationale:  
The aim of this study is to evaluate efficacy, safety, and pharmacokinetics of GLWL-01 in the 
treatment of patients with Prader-Willi Syndrome (PWS).  
Objectives/Endpoints: 
Objectives 
Endpoints 
Primary 
• Evaluate the efficacy of GLWL-01 compared 
with placebo in reducing hyperphagia-related 
behaviors after 28 days of treatment in 
patients with PWS as measured using the 
Hyperphagia Questionnaire for Clinical Trials 
(HQ-CT) 
 
• 
Posttreatment HQ-CT total score 
Secondary 
• 
Evaluate the safety and tolerability of 
GLWL-01 after 28 days of treatment in 
patients with PWS 
• 
Evaluate the efficacy of GLWL-01 compared 
with placebo in reducing hyperphagia-related 
behaviors after 28 days of treatment in 
patients with PWS as measured using the 
Caregiver Global Impression of Change 
(CGIC) 
• 
Evaluate the pharmacokinetics after single and 
multiple oral dosing of GLWL-01 in patients 
with PWS 
 
• 
Treatment-emergent adverse events 
 
 
• 
CGIC score 
 
 
 
 
• 
GLWL-01 
o 
Area under the concentration versus time 
curve from time zero to 12 hours (AUC0-12) 
o 
Maximum observed drug concentration 
(Cmax) 
Exploratory 
• 
Evaluate the effect of GLWL-01 in the 
following measures in patients with PWS 
• 
Acylated-ghrelin (AG) 
• 
Unacylated-ghrelin (UAG) 
• 
AG/UAG ratio 
• 
Body weight 
• 
Percentage fat mass 
• 
Body mass index 
• 
Waist circumference 
• 
Low-density lipoproteins 
• 
Total cholesterol 
 
 
Posttreatment: 
• 
AG 
• 
UAG 
• 
AG/UAG 
• 
Body weight 
• 
Percentage fat mass 
• 
Body mass index 
• 
Waist circumference 
• 
Low-density lipoproteins 
• 
Total cholesterol 
 
 
 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
Summary of Study Design:   
Study GLWL-PWS is a multicenter, double-blind, randomized, placebo-controlled, crossover 
study of GLWL-01 in patients with PWS.  
The study consists of 5 periods, including 2 active treatment periods, as depicted below: 
Period 
Phase 
Duration 
Screening  
NA 
28 days 
Treatment Period 1 
Single-blind placebo lead-ina 
14 days 
 
Double-blind treatment phaseb 
28 days 
Washout 
NA 
28 days 
Treatment Period 2 
Single-blind placebo lead-ina 
14 days 
 
Double-blind treatment phaseb 
28 days 
Follow-up 
NA 
14 days 
Abbreviation:  NA = not applicable 
a Only patient/caregiver will be blinded. 
b Both investigator and patient/caregiver will be blinded. 
 
Patients and caregivers will be required to visit the site on 68 occasions at Visits 1, 3, 4, 5, 8, 9, 
10, and 11.  Patients and caregivers (but not the patients) will be required to visit the site on 2 
additional occasions at Visits 2 and 7 will be required to participate in phone calls with the site at 
Visits 2, 4, 6, and 79. 
Treatment Arms and Duration: 
Patients will be randomized to 1 of 2 treatment sequences; GLWL-01/placebo or 
placebo/GLWL-01 (Treatment Period 1 double-blind treatment phase/Treatment Period 2 
double-blind treatment phase).  During single-blind placebo lead-in phases, patients will receive 
3 capsules of 150-mg placebo twice daily (BID) for 14 days.  During double-blind treatment 
phases, patients will receive 3 capsules of 150-mg GLWL-01 (450 mg total dose) BID or 
identical placebo BID for 28 days. 
Number of Patients:  
Approximately 34 patients with PWS will be randomized.  
Statistical Analysis: 
Efficacy:  Efficacy analyses will be conducted on the randomized analysis set.  The primary 
analysis will be conducted using a restricted maximum likelihood-based, mixed-effect model 
repeated measures analysis.  The analysis will be the contrast between GLWL-01 and placebo at 
the end of the double-blind treatment phase on the primary endpoint of the posttreatment HQ-CT 
score. 
The secondary analysis will be conducted similar to the primary analysis.  The secondary 
efficacy endpoint is the CGIC. 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
Safety:  Safety analyses will be conducted on the safety analysis set.  Safety data will be 
summarized by treatment group.  Safety parameters that will be assessed include adverse events, 
clinical laboratory parameters, C-SSRS, vital signs, electrocardiogram parameters, and weight.  
The parameters will be listed and summarized using standard descriptive statistics. 
Pharmacokinetics/Pharmacodynamics:  Plasma GLWL-01 pharmacokinetic (PK) parameters will 
be calculated using noncompartmental methods after single and multiple dose administration.  
Additional PK parameters may be calculated if deemed appropriate.  Pharmacokinetic 
parameters will be summarized by dose level using descriptive statistics.  Mean and individual 
GLWL-01 plasma concentration-time curves will be represented graphically. 
Pharmacodynamics of GLWL-01 will be based on plasma AG and potentially UAG measures.  
Raw and change from baseline values will be reported and summarized for AG and potentially 
UAG. 
The PK/PD relationship of GLWL-01 with PD, efficacy, and/or safety measures may be 
explored. 


GLWL-PWS(d) Clinical Protocol 
Page 72 
GLWL-01 
2. Schedule of Activities 
 


GLWL-PWS(d) Clinical Protocol 
Page 73 
GLWL-01 
Table GLWL-PWS.1. Schedule of Activities 
Period 
Screeninga 
Treatment Period 1 
Washout 
(28 days) 
Treatment Period 2 
Follow-up 
ETc 
Phase 
 
Single-blind 
Placebo Lead-in 
Phase (14 days) 
Double-blind 
Treatment Phase 
(28 days)b 
 
Single-blind 
Placebo Lead-in 
(14 days) 
Double-blind 
Treatment Phase 
(28 days)b 
 
Visit No/ 
Type Procedure 
V1 
 
V2de 
CaregiverPhone 
V3e 
 
V4f 
Phone 
V5 
 
V6e  
Phone 
V7de 
CaregiverPhone 
V8 
 
V9f 
Phone 
V10 
 
V11 
 
Day  
-28 to -3 
1 
(±3) 
14 
(±2) 
218 
(±2) 
42 
(±2) 
56 
(±2) 
70 
(±2) 
84 
(±2) 
918 
(±2) 
112 
(±2) 
126  
(±3) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationgf 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Heighthg 
X 
 
 
 
 
 
 
 
 
 
 
 
Initial history/ preexisting conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBsAg, HCAB, HIV  
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisih 
X 
 
 
 
 
 
 
 
 
 
 
 
Substance abuse screenji 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion review 
X 
 
Xe 
 
 
 
 
 
 
 
 
 
Study drug dispensing 
 
X 
X 
 
 
 
X 
X 
 
 
 
 
Study drug administration at site 
 
 
X 
 
X 
 
 
 
 
 
 
 
Study drug accountability 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
Efficacy and Outcome Measures 
HQ-CT 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CGIC 
 
 
 
 
X 
 
 
 
 
X 
 
X 
Body weighthg 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Percentage fat mass (calipers) 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
BMI 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Waist circumference 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Vital signskj 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
12-lead ECGlk 
X 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
12-lead ECG 2 hours post-dosek 
 
 
X 
 
 
 
 
X 
 
 
 
 


GLWL-PWS(d) Clinical Protocol 
Page 74 
GLWL-01 
Period 
Screeninga 
Treatment Period 1 
Washout 
(28 days) 
Treatment Period 2 
Follow-up 
ETc 
Phase 
 
Single-blind 
Placebo Lead-in 
Phase (14 days) 
Double-blind 
Treatment Phase 
(28 days)b 
 
Single-blind 
Placebo Lead-in 
(14 days) 
Double-blind 
Treatment Phase 
(28 days)b 
 
Visit No/ 
Type Procedure 
V1 
 
V2de 
CaregiverPhone 
V3e 
 
V4f 
Phone 
V5 
 
V6e  
Phone 
V7de 
CaregiverPhone 
V8 
 
V9f 
Phone 
V10 
 
V11 
 
Day  
-28 to -3 
1 
(±3) 
14 
(±2) 
218 
(±2) 
42 
(±2) 
56 
(±2) 
70 
(±2) 
84 
(±2) 
918 
(±2) 
112 
(±2) 
126  
(±3) 
Serum pregnancy testml 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Urine pregnancy testml 
 
 
X 
 
 
 
 
X 
 
 
 
 
Clinical chemistry and hematologyih 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Lipid panel 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
AG and UAGnm 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Plasma sample collection for PK 
analysison 
 
 
X 
 
X 
 
 
 
 
 
 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations:  AE = adverse event; AG = acylated-ghrelin; BMI = body mass index; CGIC = Caregiver Global Impression of Change; C-SSRS = Columbia–Suicide Severity 
Rating Scale; ECG = electrocardiogram; EDC = electronic data capture; ET = early termination; HQ-CT = Hyperphagia Questionnaire for Clinical Trials; HBsAg = hepatitis B 
surface antigen; HCAB = hepatitis C antibody; HIV = human immunodeficiency virus; PK = pharmacokinetic; UAG = unacylated-ghrelin; V = Visit. 
a 
Screening visit must occur between -28 days to -3 days of V2. 
b 
Double-blind Treatment Phase must not exceed 28 days and patients must not take the study drug beyond 28 days.  For example, if the V3 occurs on Day 14, then 
corresponding V5 would occur on Day 42.  Similarly, if V3 occurs on Day 15 (Day 14 +1), then corresponding V5 would occur on Day 43 (Day 42 +1).  
c 
The primary reason for early termination of the patient will be entered in EDC and recorded in the patient’s source documents.  The patient will attend an early termination visit 
as soon as possible after participation ceases. 
d 
Caregiver only visit; patient does not need to attend in person. 
ed Confirm that the patient has met all inclusion/exclusion criteria.  Patients will only be dosed after the investigator has completed the appropriate protocol assessments and 
determined that it is acceptable to dose the patient. 
fe Patients/caregivers will receive phone calls from the site; no visit required.  Both patient and caregiver should be on the phone in order for the site to conduct AE assessments 
and the C-SSRS. 
gf A full physical examination with neurological assessments should be performed at Visit 1.  Symptom-driven physical examinations should be performed at V3, V4, V5, and 
V8, V9, V10,V11, and at ET.  
hg Height will only be measured at Visit 1.  Patients should be instructed to wear lightweight clothing and remove shoes during weighing.   
ih Refer to Appendix 2 for details on serum chemistry, hematology, and urinalysis clinical laboratory tests. 


GLWL-PWS(d) Clinical Protocol 
Page 75 
GLWL-01 
ji 
Substance abuse screen test to be performed at Visit 1 and additionally at any visit per investigator’s discretion. 
 
kj Vital sign assessments will include triplicate sitting blood pressure, and single pulse and body temperature.  Additional vital sign assessments may be performed as clinically 
indicated.  For visits in which both vital signs and blood samples are collected, vital signs should be obtained prior to blood collection.  Any clinically significant result of vital 
sign assessment will be documented in the source documentation and EDC as an AE. 
lk Single 12-lead ECGs to be collected according to the schedule and may be collected at any time if deemed clinically necessary.  Patients must be supine for at least 5 minutes 
prior to ECG collection.  When ECG collections are scheduled at the same time point as any other tests, ECGs, followed by vital signs, should be recorded prior to any clinical 
laboratory or PK blood sampling. 
ml For all female patients, the investigator will document potential childbearing status.  For women who are postmenopausal, a confirmatory test of serum follicule-stimulating 
hormone and estradiol levels will be done at Visit 1.  For all women of childbearing potential, a pregnancy serum test will be done at Visit 1, which must be negative to enroll.  
Subsequently, urine pregnancy tests will be done for all women of childbearing potential as indicated in the schedule; the results must be confirmed negative.  In case of a 
positive urine pregnancy test, the serum pregnancy test must be performed to confirm the pregnancy results. 
nm The blood samples for AG and UAG should be collected in the fasted state. 
on On Day 14 and Day 42, a total of 7 PK samples each day will be taken at the following times:  pre-dose, and 0.5, 1, 2, 4, 6, and between 8 and 12 hours postdose.  Times of 
sampling are intended as a guide and can be modified to accommodate clinical procedures.  Actual time of sample must be collected, as well as date and time of dosing on the 
day of PK sample collection.  For patients who discontinue early, a sample should be obtained at the ET visit.  
 
 


GLWL-PWS(d) Clinical Protocol 
Page 76 
GLWL-01 
5. Study Design 
5.1 
Overall Design 
This is a multicenter, double-blind, randomized, placebo-controlled, crossover study to evaluate 
the efficacy of GLWL-01 in patients with PWS.  The study consists of 5 periods, including 
2 active treatment periods, as depicted below:  
 
 
Abbreviations:  P = phone visit; PK = pharmacokinetic sample 
Note:  Placebo lead-in phases will be single-blinded (patient/caregiver) and treatment phases will be double-blinded 
(investigator and patient/caregiver) 
Figure GLWL-PWS.2. Illustration of study design for Clinical Protocol GLWL-PWS. 
The Screening Period allows for evaluation of inclusion/exclusion criteria.  Treatment Period 1 
consists of 2 phases:  a 14-day single-blind (patient/caregiver) placebo lead-in phase followed by 
a 28-day double-blind treatment phase.  At the conclusion of the single-blind placebo lead-in 
phase, eligible patients will be randomly assigned (in 1:1 ratio) to 1 of 2 treatment sequences:  
GWLW-01/placebo or placebo/GLWL-01 (Treatment Period 1 double-blind treatment 
phase/Treatment Period 2 double-blind treatment phase).  Following Treatment Period 1, there 
will be a 28-day Washout Period.  Treatment Period 2 also consists of 2 phases:  a 14-day 
single-blind (patient/caregiver) placebo lead-in followed by a 28-day double-blind treatment 
phase.  Following Treatment Period 2, there will be a 14-day Follow-up Period (see 
Figure GLWL-PWS.1). 


GLWL-PWS(d) Clinical Protocol 
Page 77 
GLWL-01 
Patients and caregivers will be required to visit the site on 68 occasions at Visits 1, 3, 4, 5, 8, 9, 
10, and 11.  Patients and caregivers (but not the patients) will be required to visit the site on 2 
additional occasions at Visits 2 and 7 will be required to participate in phone calls with the site at 
Visits 2, 4, 6, and 79. 
Study governance considerations are described in detail in 3.1 Appendix 3. 
6.3 
Lifestyle Restrictions 
Consumption of foods and beverages containing the following substances will be limited or 
prohibited as indicated: 
• xanthine/caffeine:  throughout the study, patients are required to maintain their regular 
intake of caffeinated beverages for the duration of the study 
• Alcohol:  an average weekly alcohol intake should not exceed 21 units per week (males 
≤65 years of age) and 14 units per week (females and males >65 years of age). 
• Grapefruit/Seville orange:  14 days before first dosing and throughout the study. 
Following the morning dose on Day 14 and Day 42, and on Day 84 and Day 112, patients will 
remain ambulatory or seated upright for the first 4 hours, except when they are supine or 
semi-reclined for study procedures. 
Patients will be instructed to refrain from strenuous physical activity which could cause muscle 
aches or injury, including contact sports at any time from Visit 1 until completion of the study 
participation.  Patients should otherwise minimize changes in their activity levels during study 
participation. 
6.4 
Screen Failures 
Patients who do not meet the criteria for participation in this study (screen failure) at Visit 1 may 
be rescreened.  Individuals may be rescreened up to 1 time.  The rescreen should be at the 
discretion of the PI after discussion with sponsor medical representative.  If a rescreening is 
performed, the individual must sign a new informed consent form (ICF) and will be assigned a 
new identification number. 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
7. Treatments 
7.1 
Treatments Administered 
GLWL-01 drug product is supplied for clinical trial use as size 0 dark blue opaque capsules for 
oral administration.  Capsules will contain 150 mg of GLWL-01.  No additional excipients are 
used, with the exception of the capsule itself. 
The GLWL-01 drug product placebo will consist of microcrystalline cellulose and magnesium 
stearate filled directly into size 0 dark blue opaque capsules, identical in appearance to 
GLWL-01 150-mg capsules. 
Capsules must be taken whole. 
In Treatment Period 1, all eligible patients will undergo a single-blind (patients/caregiver) 
placebo lead-in phase, wherein they will receive 3 capsules of placebo BID for 14 days.  
Following this, patients will be randomly assigned to either GLWL-01 450 mg BID/placebo or 
placebo/GLWL-01 450 mg BID treatment sequence.  During Treatment Period 1, patients will 
receive 3 capsules of 150-mg GLWL-01 (450-mg total dose) or identical matching placebo BID 
for 28 days.   
Before Treatment Period 2, patients will undergo a 28-day Washout Period following which all 
patients will receive 3 capsules of placebo BID during the 14-day single-blind placebo lead-in 
phase.  
During Treatment Period 2 double-blind treatment phase, patients will receive 3 capsules of 
150-mg GLWL-01 (450-mg total dose) or identical matching placebo BID for 28 days.  The 
double-blind treatment phases in both treatment periods must not exceed 28 days and patients 
must not administer the double-blind study drug beyond 28 days.  The study drugs can be 
administered in fed or fasted conditions. 
The investigator or designee is responsible for 
• explaining the correct use of the study drug to patients and caregivers; 
• verifying that instructions are followed properly; 
• maintaining accurate records of study drug dispensation and collection; 
• and returning all unused medications to sponsor or its designee at the end of the study. 
Note:  In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical materials.  


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
8. Discontinuation Criteria 
Patient participation in the study may be discontinued for any of the following reasons: 
• Enrollment in any other clinical study involving any study drug or enrollment in any 
other type of medical research judged not to be scientifically or medically compatible 
with this study. 
• Investigator’s decision:  the investigator decides that the patient should be discontinued 
from the study. 
• Patient’s/caregiver’s decision:  the patient or caregiver requests to be discontinued 
from the study. 
• Sponsor’s decision:  GLWL stops the study or stops the patient’s participation in the 
study for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and GCP. 
• Adverse event:  any SAE or a significant change in a laboratory value occurs that merits 
the study drug being discontinued and necessitates appropriate measures being taken.  In 
this case, the sponsor is to be notified immediately. 
• Hepatic event or liver test abnormality:  Patients who are discontinued from using 
study drug due to a hepatic event or liver test abnormality should have additional hepatic 
safety data collected via electronic data entry. 
Discontinuation of the study drug for abnormal liver test results should be considered by 
the investigator when a patient meets 1 of the following conditions after consultation 
with the sponsor medical representative: 
o ALT or AST >5X ULN 
o ALT or AST >3X ULN along with 1 of the following criteria: 
 sustained for more than 2 weeks or 
 total bilirubin level (TBL) >2X ULN or 
 prothrombin time >1.5X ULN or 
 the appearance of fatigue, nausea, vomiting, right upper-quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%) 
o ALP >3X ULN 
o ALP >2.5X ULN and TBL >2X ULN 
o ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• Marked prolongation of the QT/QTc interval >500 ms or >60 ms over baseline, judged 
medically significant following repeat ECG after 5 minutes of rest from the initial ECG. 
• A clinically significant systemic hypersensitive reaction occurs following administration 
of the study drug (e.g., study drug-related symptomatic bronchospasm, allergy-related 
edema/angioedema, or hypotension), that requires parenteral medication, does not 
respond to symptomatic medication, or result in clinical sequelae or an anaphylactic 
reaction. 
• An elevated troponin I level (greater than 0.04 ng/mL); the patient must be referred for 
further evaluation. 


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GLWL-01 
• Patient has stopped eating or drinking for more than 24 hours. 
• Requirement of prohibited concomitant medication. 
• Patient failure to comply with protocol requirements or study-related procedures. 
• Termination of the study by the sponsor or regulatory authorities.  
The clinical report will include reason(s) for patient withdrawals as well as details relevant to the 
patient withdrawal. 
Patient discontinuing from the study prematurely for any reason should complete AE and other 
follow-up procedures per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol. 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site. 


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Appendix 5. Sampling Summary 
This table summarizes the approximate number of samples and volumes for all sampling and 
tests during the study.  Fewer samples may actually be taken, but this will not require a protocol 
amendment. 
Protocol GLWL-PWS Sampling Summary 
 
Purpose 
Sample 
Type 
Maximum Amount 
per Sample 
Maximum 
Number of 
Samples 
Maximum 
Total Amount 
Screening testsa 
Blood 
21 mL 
1 
21 mL 
Standard laboratory testsa 
Blood 
2 mL 
5 
10 mL 
Drug concentration 
Blood 
2 mL 
14 
28 mL 
AG and UAG samples 
Blood 
4 mL 
5 
20 mL 
On-study serum chemistry 
(includes serum thyroid-
stimulating hormone, lipid 
panel, troponin, and serum 
pregnancy when done at the 
same time) 
Blood 
15 mL 
5 
75.0 mL 
Total 
Blood 
- 
- 
154.0 mL 
Hepatic monitoringb 
Blood 
3 - 30 mL 
- 
- 
a Additional samples may be drawn if needed for safety purposes. 
b Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with Lilly-designated Medical Monitor. 
 
 
 


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Appendix 8. 
Protocol Amendment GLWL-PWS(c) 
Summary [A Phase 2 Study to Evaluate Efficacy, Safety, 
and Pharmacokinetics of GLWL-01 in the Treatment of 
Patients with Prader-Willi Syndrome] 
Overview 
Protocol GLWL-PWS [A Phase 2 Study to Evaluate Efficacy, Safety, and Pharmacokinetics of 
GLWL-01 in the Treatment of Patients with Prader-Willi Syndrome] has been amended.  The 
new protocol is indicated by amendment (c) and will be used to conduct the study in place of any 
preceding version of the protocol. 
The overall changes and rationale for the changes made to this protocol are as follows: 
• Troponin has been listed separately in the Schedule of Activities for clarification 
purposes; no changes have been made to laboratory draws 
• Exclusion Criterion #23c flexibility added.  The previous language explicitly prohibited 
enrolling patients on “any medications that prolong the QT/QTc interval.”  
o The original request for adding the QTc prolonging medications to the exclusion 
criteria came from HC (Control #208160, CR File Number:  HC6-24-c208160); 
and prompted amendment (a).  However, the suggested wording from Health 
Canada stated the medications could be used “with caution,” which was not 
accurately reflected in the amended protocol.  
o In addition, the criterion was prior to availability of QT/QTc data.  We currently 
have data from 9 enrolled Prader-Willi patients that have completed between 5 
and 9 visits in this study, in addition to 38 diabetes patients that received GLWL 
in a previous study (GLWL-SMP).  
o There has been no QT/QTc prolongation observed to date. 
1. In addition to regular ECGs to assess intervals, we are measuring 
troponins 
2. Prolongation of the QT/QTc interval >500 ms or >60 ms over baseline, 
judged medically significant following repeat ECG after 5 minutes of rest 
from the initial ECG remains a discontinuation criterion. 
o At this time, we feel there is enough evidence to proceed with the new wording 
for Exclusion Criteria #23c of, “Any medications that prolong the QT/QTc 
interval will be excluded, unless the patient has been stable on the medication for 
at least 3 months and has a QTc <450 msec at Visit 1 and Visit 3.” 


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• Section 7.7 Concomitant Therapy verbiage has been updated to allow inclusion of 
patients on stable doses of medications that have been publicly noted to potentially cause 
QTc prolongation. 
 
 


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GLWL-01 
Revised Protocol Sections 
Note: 
Deletions have been identified by strikethroughs or grayed out for figures. 
Additions have been identified by the use of underscore. 
 
 
 


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Table GLWL-PWS.4. Schedule of Activities  
Period 
Screeninga 
Treatment Period 1 
Washout 
(28 days) 
Treatment Period 2 
Follow-up 
ETc 
Phase 
 
Single-blind 
Placebo 
Lead-in 
Phase 
(14 days) 
Double-blind 
Treatment Phase 
(28 days)b 
 
Single-blind 
Placebo 
Lead-in 
(14 days) 
Double-blind 
Treatment Phase 
(28 days)b 
 
Visit No/ 
Type Procedure 
V1 
 
V2e 
Phone 
V3d 
 
V4  
 
V5 
 
V6 e 
Phone 
V7e 
Phone 
V8 
 
V9  
 
V10 
 
V11 
 
Day  
-28 to -3 
0 
(±3) 
14 
(±2) 
21 
(±2) 
42 
(±2) 
56 
(±2) 
70 
(±2) 
84 
(±2) 
91 
(±2) 
112 
(±2) 
126  
(±3) 
12-lead ECG 2 hours post-dose k 
 
 
X 
 
 
 
 
X 
 
 
 
 
Serum pregnancy testl 
X 
 
 
 
 
 
 
 
 
X 
 
X 
Urine pregnancy testl 
 
 
X 
 
 
 
 
X 
 
 
 
 
Clinical chemistry and hematologyh 
X 
 
X 
X 
X 
 
 
X 
X 
X 
 
X 
Troponin 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
 
Lipid panel 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
AG and UAGm 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Plasma sample collection for PK 
analysisn 
 
 
X 
 
X 
 
 
 
 
 
 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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6.2 
Exclusion Criteria 
23. Unable to refrain from or anticipates the use of 
a. Any drugs known to be significant inhibitors of cytochrome P450 (CYP)3A 
enzymes and/or P-glycoprotein (P-gp) including regular consumption of 
grapefruit or grapefruit juice for 14 days prior to the first dose of study medication 
and throughout the study.  Appropriate sources will be consulted by the principal 
investigator (PI) or designee to confirm lack of PK or pharmacodynamic (PD) 
interaction with study medication.  Acetaminophen (up to 2 g per 24-hour period) 
may be permitted during the study. 
b. Any drugs known to be significant inducers of CYP3A enzymes and/or P-gp, 
including St. John’s Wort, for 28 days prior to the first dose of study medication 
and throughout the study.  Appropriate sources will be consulted by the PI or 
designee to confirm lack of PK/PD interaction with study medication. 
c. Any medications that prolong the QT/QTc interval, unless the patient has been on 
a stable dose of said medication for at least 3 months and has a QTc <450 msec at 
Visit 1 and Visit 3. 
 
7.7 
Concomitant Therapy 
Patients may not take any medication (including over-the-counter products), herbal products, or 
vitamin supplements, which are CYP3A and/or P-gp inhibitors for 14 days prior to dosing and 
throughout the study.  In cases that require the use of such medication for the treatment of an AE 
or comorbidity, GLWL-01 dosing must be terminated before the CYP3A inhibitor can be started. 
Medications that prolong the QT/QTc interval are prohibited acceptable, per the investigator’s 
judgement.  A list of medications with a potential for QTc prolongation will be provided 
separately and updated as data evolves to the investigators. 
If the need for the initiation of other medication arises during the study, the investigator must 
consult with sponsor medical representative and such medication change must be reported in the 
EDC. 
All medications taken by patients during the course of the study will be recorded.  Concomitant 
medications will be listed by treatment and coded using the most current World Health 
Organization drug dictionary. 
 
 
 


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Appendix 9. 
Protocol Amendment GLWL-PWS(d) 
Summary [A Phase 2 Study to Evaluate Efficacy, Safety, 
and Pharmacokinetics of GLWL-01 in the Treatment of 
Patients with Prader-Willi Syndrome] 
Overview 
Protocol GLWL-PWS [A Phase 2 Study to Evaluate Efficacy, Safety, and Pharmacokinetics of 
GLWL-01 in the Treatment of Patients with Prader-Willi Syndrome] has been amended.  The 
new protocol is indicated by amendment (d) and will be used to conduct the study in place of any 
preceding version of the protocol. 
The overall changes and rationale for the changes made to this protocol are as follows: 
• Language regarding QTc prolongation medications in Section 7.7, Concomitant Therapy, 
has been clarified at the request of Health Canada. 
 
 


GLWL-PWS(d) Clinical Protocol 
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GLWL-01 
Revised Protocol Sections 
Note: 
Deletions have been identified by strikethroughs or grayed out for figures. 
Additions have been identified by the use of underscore. 
 
 
 


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GLWL-01 
7.7 
Concomitant Therapy 
Patients may not take any medication (including over-the-counter products), herbal products, or 
vitamin supplements, which are CYP3A and/or P-gp inhibitors for 14 days prior to dosing and 
throughout the study.  In cases that require the use of such medication for the treatment of an AE 
or comorbidity, GLWL-01 dosing must be terminated before the CYP3A inhibitor can be started. 
Medications that prolong the QT/QTc interval are allowed provided the patient has been on a 
stable dose of said medication for at least 3 months and has a QTc < 450 msec at Visit 1 and 
Visit 3.acceptable, per the investigator’s judgement.  A list of medications with a potential for 
QTc prolongation will be provided separately to the investigators. 
If the need for the initiation of other medication arises during the study, the investigator must 
consult with sponsor medical representative and such medication change must be reported in the 
EDC. 
All medications taken by patients during the course of the study will be recorded.  Concomitant 
medications will be listed by treatment and coded using the most current World Health 
Organization drug dictionary. 
 

SAP_001.pdf: 
GLWL-PWS Statistical Analysis Plan 
A Phase 2 Study to Evaluate Efficacy, Safety, and Pharmacokinetics of GLWL-01 in the 
Treatment of Patients with Prader-Willi Syndrome (Version 2 Final) 
NCT03274856 
Approved:  March 19, 2019


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Statistical Analysis Plan 
GLWL-PWS 
 
 A Phase 2 Study to Evaluate Efficacy, Safety, and 
Pharmacokinetics of GLWL-01 in the Treatment of Patients 
with Prader-Willi Syndrome 
 
 
Version 2 Final 
 
19 March 2019 
 
Prepared for 
 
 
GLWL Research Inc. l CHORUS 
 
GLWL Research Inc. 
Montreal, Quebec, Canada 
 
 
 
 
 
 
 
 
 
Prepared by 
 
55 Corporate Woods 
9300 West 110th Street, Suite 550 
Overland Park, Kansas  66210 


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Table of Contents 
Description 
Page 
ABBREVIATIONS/DEFINITIONS .............................................................................. 4 
1. 
Introduction and Objectives ................................................................................ 5 
1.1. 
Introduction .......................................................................................................... 5 
1.2. 
Study Objectives ................................................................................................... 5 
1.3. 
Determination of Sample Size ............................................................................. 6 
2. 
General Statistical Methodology and Conventions ........................................... 6 
2.1. 
Randomization Schedule and Unblinding Plan ................................................. 7 
2.2. 
Analysis Populations ............................................................................................ 7 
2.3. 
Definition of Study Time Points .......................................................................... 8 
2.3.1. Reporting Periods for Concomitant Medications and Safety Endpoints ........ 8 
2.4. 
Handling of Dropouts and Missing Data ............................................................ 8 
2.5. 
Adjustment for Multiple Centers ........................................................................ 9 
2.6. 
Interim Analysis and Adjustment for Multiplicity ........................................... 9 
2.7. 
Coding of Concomitant Medications and Adverse Events ............................... 9 
2.8. 
Reporting Conventions ........................................................................................ 9 
2.9. 
Changes to the Planned Analyses ...................................................................... 10 
3. 
Patient Accounting and Disposition .................................................................. 10 
3.1. 
Patient Accounting ............................................................................................. 10 
3.2. 
Patient Disposition .............................................................................................. 10 
4. 
Baseline Characteristics ..................................................................................... 11 
4.1. 
Demographics ..................................................................................................... 11 
4.2. 
Baseline Anthropometrics ................................................................................. 11 
4.3. 
Medical History .................................................................................................. 11 
5. 
Concomitant Medications .................................................................................. 11 
6. 
Efficacy Analyses ................................................................................................ 11 
6.1. 
Primary Efficacy Analysis ................................................................................. 12 
6.1.1. Sensitivity Analyses for the Primary Efficacy Variable ................................. 12 
6.2. 
Secondary Efficacy Analyses ............................................................................. 12 


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6.2.1. Additional analyses from the HQ-CT ............................................................... 12 
6.2.2. Analyses of the Caregiver Global Impression of Change ............................... 13 
7. 
Safety Analyses ................................................................................................... 13 
7.1. 
Study Medication Exposure and Treatment Compliance .............................. 13 
7.1.1. Extent of Exposure ............................................................................................. 13 
7.1.2. Treatment Compliance ...................................................................................... 13 
7.2. 
Adverse Events .................................................................................................... 13 
7.2.1. Treatment-Emergent Adverse Events .............................................................. 14 
7.2.2. Treatment-Related Treatment-Emergent Adverse Events ............................ 14 
7.2.3. Serious Treatment-Emergent Adverse Events ................................................ 14 
7.2.4. Treatment-Emergent Adverse Events Resulting in Death ............................. 14 
7.2.5. Treatment-Emergent Adverse Events Leading to Study Drug 
Discontinuation ................................................................................................... 14 
7.2.6. Treatment-Emergent Adverse Events by Maximal Severity ......................... 15 
7.3. 
Clinical Laboratory Summaries ........................................................................ 15 
7.4. 
Vital Signs ............................................................................................................ 15 
7.5. 
Electrocardiogram Summaries ......................................................................... 15 
7.6. 
Columbia Suicide Severity Rating Scale .......................................................... 16 
8. 
Exploratory Analyses ......................................................................................... 16 
9. 
Pharmacokinetic Analyses ................................................................................. 16 
References ....................................................................................................................... 17 
 
 
 


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ABBREVIATIONS/DEFINITIONS 
Abbreviation 
Definition 
AG 
acylated-ghrelin (AG) 
AE 
adverse event 
AUC0-12 
Area under the concentration versus time curve from time zero to 12 hours 
BMI 
body mass index 
CGIC 
Caregiver Global Impression of Change 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
eCRF 
electronic case report form 
GOAT 
ghrelin-O-acyltransferase 
HQ-CT 
Hyperphagia Questionnaire for Clinical Trials 
IRT 
Interactive response technology 
MedDRA™ 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed effects model repeated measures 
PK 
pharmacokinetic 
PWS 
Prader-Willi Syndrome 
QT 
time between the start of the Q wave and the end of the T wave in the heart's 
electrical cycle 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAE 
serious adverse event 
SAP 
Statistical analysis plan 
SOC 
system organ class 
TEAE 
treatment emergent adverse event 
UAG 
unacylated-ghrelin  
WHODD 
World Health Organization Drug Dictionary 
 
 
 
 
 


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1. 
INTRODUCTION AND OBJECTIVES 
1.1. 
Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the analysis variables and 
statistical procedures that will be used to analyze and report the results from a Phase 2 study 
evaluating the safety and efficacy of GLWL-01, an inhibitor of the ghrelin-O-acyltransferase 
(GOAT) enzyme that converts UAG into AG, in patients with Prader-Willi Syndrome (PWS). 
This SAP is based on the amended protocol, Protocol GLWL-PWS(d), which was approved on 
27 June 2018.  
Changes to the protocol that impact the design, the data collected, or the statistical methods and 
that occur after the finalization of this SAP may require an amendment to the approved SAP. 
Similarly, changes to the planned analysis variables or statistical methods described in the 
approved SAP may also require an amendment to the SAP.  
The formats for the tables, listings, and figures described in this SAP are provided in a 
companion document. Changes to the formats of these reports that are decided after the 
finalization of the SAP will not require an amendment. In addition, any additional supportive or 
exploratory analyses requested after SAP approval will not require amendment of the SAP. 
These additional analyses will be described in the clinical study report (CSR).  
Please see the study protocol for details about the study design, procedures, and schedule of 
assessments and see the electronic case report form (eCRF) for details about variables collected 
and their possible values. 
1.2. 
Study Objectives 
Table 1 shows the objectives and endpoints of the study. 
Table 1.  
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• Evaluate the efficacy of GLWL-01 compared 
with placebo in reducing hyperphagia-related 
behaviors after 28 days of treatment in patients 
with PWS as measured using the Hyperphagia 
Questionnaire for Clinical Trials (HQ-CT) 
 
• Post-treatment HQ-CT total score 
Secondary 
• Evaluate the safety and tolerability of 
GLWL-01 after 28 days of treatment in patients 
with PWS  
 
• Treatment-emergent adverse events  


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Objectives 
Endpoints 
• Evaluate the efficacy of GLWL-01 compared 
with placebo in reducing hyperphagia-related 
behaviors after 28 days of treatment in patients 
with PWS as measured using the Caregiver 
Global Impression of Change (CGIC)  
• CGIC score  
• Evaluate the pharmacokinetics after single and 
multiple oral dosing of GLWL-01 in patients 
with PWS 
• GLWL-01  
- Area under the concentration 
versus time curve from time 0 to 
12 hours (AUC0-12)  
- Maximum observed drug 
concentration (Cmax) 
Exploratory 
• Evaluate the effect of GLWL-01 in the 
following measures in patients with PWS  
 
• Posttreatment:  
- Acylated-ghrelin (AG)  
- Unacylated-ghrelin (UAG)  
- AG/UAG ratio  
- Body weight  
- Percentage fat mass  
- Body mass index  
- Waist circumference  
- Low-density lipoproteins  
- Total cholesterol 
- Blood glucose 
- AG  
- UAG  
- AG/UAG  
- Body weight  
- Percentage fat mass  
- Body mass index  
- Waist circumference  
- Low-density lipoproteins  
- Total cholesterol 
- Blood glucose 
1.3. 
Determination of Sample Size 
Approximately 34 patients were planned to be randomized to 1 of 2 treatment sequences 
(GLWL-01/placebo or placebo/GLWL-01) in a 1:1 ratio. Thirty-four patients would provide 
approximately 80% power to detect an effect size of 0.75 for the HQ-CT total score using a 2-
sided exact paired t-test with an α=0.05, assuming 10% drop out. 
2. 
GENERAL STATISTICAL METHODOLOGY AND CONVENTIONS 
Chorus has designated EMB Statistical Solutions to generate the statistical analyses detailed in 
this SAP. All computations for statistical analyses will be performed using SAS® software, 
Version 9.4 or later. All SAS programs used in the production of statistical summary outputs will 
be validated with independent programming prior to finalization. In addition, all program outputs 
will be independently reviewed. The validation process will be used to confirm that all data 


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manipulations and calculations were accurately done. Once validation is complete, a senior 
statistical reviewer will perform a final review of the documents to ensure the accuracy and 
consistency with this plan and consistency within tables. Upon completion of validation and 
quality review procedures, all documentation will be collected and filed by the project statistician 
or designee. 
Before implementation of parametric methods of analysis, the distribution of analysis variables 
will be examined to determine if model assumptions are satisfied. Transformations or 
nonparametric methods of analysis may be used if warranted. However, in some cases, 
nonparametric analysis may be the initially proposed method due to the expected distribution of 
response. Whenever alternative methods of analysis are required, the description of the new 
method along with the rationale for its use will be documented in the CSR. 
The eCRF data for all patients will be provided in Standard Data Tabulation Model (SDTM) 
datasets. Any additional data listings supplied as part of the CSR will be sorted by investigative 
site and patient identification number, and patients will be identified in the listings by the 
investigator number concatenated with the patient number. 
2.1. 
Randomization Schedule and Unblinding Plan 
This is a double-blind, 2-period, crossover study in which the patients, caregivers, investigators, 
and study site personnel will be blinded to treatment allocation. ClinPhone will be responsible 
for building the interactive response technology (IRT) system that randomly assigns treatment 
sequences (either Placebo/GLWL or GLWL/Placebo) to patients.  
To preserve the blinding of the study, only a minimum number of Chorus personnel will see the 
randomization table and treatment assignments before the study is complete. This limited group 
will have access to unblinded treatment information to ensure the safety of patients in the study 
and to manage clinical trial supplies for the investigative sites. Site personnel and patients will 
remain blinded until the study is complete.  
Emergency unblinding of site personnel may be performed through the IRT system. This option 
may be used ONLY if the patient’s well-being requires knowledge of the patient’s treatment 
assignment. All calls resulting in an unblinding event are recorded and reported by the IRT 
system. 
Unblinding will occur after the last patient completes the study and all data management 
activities have been completed (i.e. data entered, coding completed, and all queries resolved). 
2.2. 
Analysis Populations 
The Entered Population is defined as all patients who signed informed consent. The Evaluable 
Population is defined as all randomized patients who received at least one dose of double-blind 
study drug. 
The Entered Population will be used to summarize enrollment at the study sites, for the summary 
of patient disposition, and in all listings. Otherwise, tables and figures will summarize the 
Evaluable Population according to the treatment the patient actually received. Any discrepancies 
between the randomized treatment and the treatment actually received will be noted in the 
listings. 


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2.3. 
Definition of Study Time Points 
For the summarization of demographic and background characteristics, the value of an endpoint 
will be the last measurement taken prior to the first dose of double-blind study drug during 
Treatment Period 1 on Study Day 14.  
Baseline values will be determined separately for each treatment phase. The baseline values for 
each double-blind treatment phase will include the last measurements taken prior to or on the 
date of the first dose of the double-blind study drug, on Study Day 14 and Study Day 84, unless 
the time of the assessment/event was after the time the dose was administered. Treatment phase 
day will be defined separately for each treatment phase as  
Treatment phase day = Visit Date – Date of 1st dose of double-blind study drug. 
Therefore, Study Day 14 and Study Day 84 will be considered Treatment Phase Day 0 (i.e. 
Baseline) for Treatment Phase 1 and Treatment Phase 2, respectively. Similarly, Study Day 42 
and Study Day 112 will be considered Treatment Phase Day 28 for Treatment Phase 1 and 
Treatment Phase 2, respectively. 
2.3.1. Reporting Periods for Concomitant Medications and Safety Endpoints 
For adverse events and concomitant medications, and for unscheduled safety assessments (e.g. 
laboratory measurements), the reporting period for each treatment phase will include all data 
recorded after the first dose of double-blind study drug up to 14 days after the last dose of 
double-blind study drug. 
2.4. 
Handling of Dropouts and Missing Data 
For the analyses of endpoints that are collected longitudinally, a last observation analysis may be 
performed by carrying forward the last post-baseline assessment within a treatment phase. In 
addition, for many of the endpoints, mixed effect model repeated measures (MMRM) analyses 
will be performed to mitigate the impact of missing data, assumed to be missing at random. 
If only a missing or partial date for AEs or concomitant medications is available and a complete 
date is required for calculations, the following algorithms will be applied: 
• For the start date:  
- If year, month, and day are missing then use the minimum of the patient's first visit date 
or the consent date.  
- If either only month or month and day are missing then use January 1.  
- If only day is missing, impute the first day of the month.  
• For the end date:  
- If year, month, and day are missing then use the patient's last visit date.  
- If either only month or month and day are missing then use December 31.  
- If only day is missing then use the last day of the month.  
- Do not expand the record past the patient's last visit.  


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The original missing or partial date, the imputed complete date, and the indicator variable that 
indicates which dates were imputed will be retained in the database.  
For vital signs and electrocardiograms, for which the time of assessment is to be captured, 
assessments made on Study Day 14 or Study Day 84 will be assumed to have occurred prior to 
dosing (i.e. as planned) if the time of the assessment is missing. For adverse events, for which 
the time of onset is to be captured, adverse events that start on Study Day 14 or Study Day 84 
will be assumed to have occurred after dosing if the time of the assessment is missing. 
2.5. 
Adjustment for Multiple Centers 
The randomization is not stratified by investigative site, and the variable “site” will not be 
included in the statistical models by default. 
2.6. 
Interim Analysis and Adjustment for Multiplicity 
There are no planned interim analyses for this study, and there is only a single primary efficacy 
endpoint. Because this is a Phase 2 study, no adjustments for multiplicity will be made for 
statistical tests of secondary or exploratory endpoints. 
2.7. 
Coding of Concomitant Medications and Adverse Events 
Adverse events (AEs) and conditions/procedures from the patients’ medical histories will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA™). Concomitant 
medications will be coded using the World Health Organization Drug Dictionary (WHODD). 
The versions of these dictionaries used for reporting will be provided in the CSR. 
2.8. 
Reporting Conventions 
This section details the general conventions to be used for the statistical analyses. Departures 
from these general conventions will be provided in the specific detailed sections of this analysis 
plan. The following conventions will be applied to all data presentations and analyses:   
• Data will be summarized by treatment sequence (i.e. Placebo/GLWL, GLWL/Placebo, and 
Overall) and/or treatment (i.e. Placebo and GLWL) as appropriate : 
• Continuous variables will generally be summarized by the number of patients, mean, 
standard deviation, median, minimum, and maximum. Exceptions to these conventions will 
be specifically noted. Categorical variables will be summarized by the number and percent of 
patients within each category. 
• All mean and median values will be formatted to one more decimal place than the measured 
value. 
• Standard deviation values will be formatted to two more decimal places than the measured 
value. 
• Minimum and maximum values will be presented with the same number of decimal places as 
the measured value. 
• The number and percent of responses will be presented in the form XX (XX), where the 
percentage is in parentheses. Percentages will be rounded to the nearest percent. In the case 


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of a frequency of zero, the frequency and percentage will be presented as 0 rather than 
0 (0%). 
• All summary tables will include the analysis population sample size (i.e. number of patients) 
in each treatment group or sequence. 
• Date variables will be formatted as ddMMMYYYY for presentation. 
2.9. 
Changes to the Planned Analyses 
Note that what is now called the Evaluable Population was called the Randomized Population 
in the protocol. 
Blood glucose was added to the list of exploratory endpoints. 
The determination of a treatment-emergent adverse event has been changed from that in the 
protocol, because the way adverse events are actually being captured is not as was anticipated. 
Specifically, an ongoing adverse event that worsens during the study will be captured as a new 
adverse event, so that adverse events that start during one period of the trial and get worse during 
a different period of the trial (which defines treatment-emergent) will have separate records that 
will be summarized separately. 
The statistical analyses will be performed as 1-sided tests rather than 2-sided tests as originally 
planned, because enrollment was stopped prior to obtaining the intended 34 patients. With the 
anticipated 19 patients, there is at least 70% power for the primary treatment comparison, which 
is still considered acceptable for a proof of concept trial. 
3. 
PATIENT ACCOUNTING AND DISPOSITION 
3.1. 
Patient Accounting 
For each study site, the number of patients entered and randomized (overall and by treatment 
sequence) will be presented. The date of the first patient visit and the last patient visit for each 
study site will also be provided. These dates and patient totals will also be summarized for the 
whole study and by country.  
A list of protocol deviations that could potentially impact the analysis of the study will be 
determined during the conduct of the study by study team members who are blinded to assigned 
study treatment. The number and percentage of patients with each deviation will be tabulated 
overall and by treatment using the Evaluable Population. 
3.2. 
Patient Disposition 
The disposition of patients in the Evaluable Population will be presented separately. The 
summaries will include the number of patients randomized and randomized but not treated, as 
well as the number of patients treated in each treatment phase. The number of patients 
completing the study will be presented. For patients who do not complete the study, the reasons 
for study discontinuation as well as the study stage of discontinuation (i.e. Placebo Lead-in 
Phase 1, Treatment Phase 1, Washout, Placebo Lead-in Phase 2, Treatment Phase 2, and Follow-
up) will be tabulated. 


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4. 
BASELINE CHARACTERISTICS 
Demographic data, baseline body measurements, and medical history will be summarized using 
descriptive statistics. Patients who are missing measurements of the baseline variable being 
analyzed will not be included in the summary for that variable. 
4.1. 
Demographics 
Year of birth, gender, race, and ethnicity are collected during screening. As only the year of birth 
was collected, the patient’s birthday will be approximated assuming the date as 1 July. Age at 
study entry will be based on the age of the patient on the date the informed consent is signed. 
Age at study entry will be analyzed as a continuous variable. Sex will be analyzed as a 
categorical variable. Patient race will be captured using multiple racial categories (i.e. American 
Indian or Alaskan Native, Asian, Black or African American, Native Hawaiian or other Pacific 
Islander, White, and Unwilling to provide). Patients selecting more than one race category will 
tabulated using the category Multiple. The response for ethnicity could be Hispanic or Latino, 
Non-Hispanic or Non-Latino, or Unwilling to provide. Ethnicity will be analyzed as a categorical 
variable. 
4.2. 
Baseline Anthropometrics 
The body measurements height, weight, body mass index (BMI), waist circumference, and 
percent fat mass will be recorded at baseline. Each will be reported as a continuous variable.  
4.3. 
Medical History 
The number and percent of patients reporting relevant medical history will be presented at the 
system organ class (SOC) and preferred term (PT) levels.  
5. 
CONCOMITANT MEDICATIONS 
Concomitant medications will be defined as medications taken during either treatment phase 
reporting period. This includes medications for which the start date is during a treatment phase 
reporting period, or for which the start date is before the date of the first dose of double-blind 
study drug but the end date is either during the treatment phase reporting period, after the end of 
the treatment phase reporting period, or for which the medication is on-going. Those medications 
where the stop date is documented as prior to the date of the first dose of double-blind study drug 
during the first treatment phase will be classified as prior medications.  
6. 
EFFICACY ANALYSES 
Efficacy analyses for this study will be based on the findings from two instruments. First, the 
HQ-CT is a validated tool developed specifically for PWS to capture observations of problematic 
behaviors related to food. It consists of 9 items, with a 2-week recall period. The scale provides a 
composite value from 9 questions, each rated on a scale of 0 to 4 units (total range of score of 0 
to 36; Fehnel et al. 2015).  
Second, the CGIC is a single-item question rated on a 0 to 7 scale directed at the caregiver 
asking for an assessment of the overall improvement of patients with PWS. 


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Both of these assessments will be collected longitudinally during the study. 
All efficacy analyses will be performed using the Evaluable Population. The method of analysis 
or statistical technique employed to address missing data will be described separately for each 
variable. Presentations of efficacy will include the number of patients with data at each time 
point plus related statistics derived from the analysis. 
All statistical tests will be 1-sided. 
6.1. 
Primary Efficacy Analysis 
The primary efficacy analysis will examine the contrast between GLWL-01 and placebo for the 
post-treatment HQ-CT total score at the end of the double-blind treatment phase. 
The primary analysis will be conducted using a restricted maximum likelihood-based, mixed-
effect model repeated measures analysis. The model for the primary analysis will include the 
fixed, categorical effects of sequence, period, and treatment, as well as the continuous, fixed 
covariate of the baseline Treatment Phase 1 HQ-CT score minus the baseline Treatment Phase 2 
HQ-CT score (diff) and the interaction of period-by-diff (Mehrotra, 2014). 
An unstructured covariance matrix will be used to model the within-patient errors. 
Satterthwaite’s approximation will be used to estimate the denominator degrees of freedom. The 
significance of differences in least-square means will be based on Type III tests using the 
observed population margins. The analyses will be performed using the SAS procedure PROC 
MIXED. 
The tabular output for these MMRM analyses will present the least squares means, standard 
errors, and 95% confidence intervals for each marginal main effect. Pairwise contrasts of the 
least squares means between GLWL-01 and Placebo will also be provided at each time point 
using LSMESTIMATE statements.  
Descriptive statistics for the HQ-CT score and the within-treatment phase changes from baseline 
will be provided by treatment and time point. 
6.1.1. Sensitivity Analyses for the Primary Efficacy Variable 
Sensitivity analyses of the primary endpoint may be performed if the primary efficacy analysis 
demonstrates a difference between GLWL-01 and placebo. These contingent analyses will be 
detailed in an addendum to this SAP. 
6.2. 
Secondary Efficacy Analyses 
6.2.1. Additional analyses from the HQ-CT 
The last observation of the HQ-CT in the treatment phase will be separately analyzed using the 
same methods used for the primary efficacy endpoint. Similarly, the sixth and ninth items of the 
HQ-CT comprise a measure of the severity of hyperphagia, which will be analyzed using the 
same methods.  


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6.2.2. Analyses of the Caregiver Global Impression of Change 
The CGIC will be analyzed using similar methods used for the primary efficacy endpoint. The 
analysis of the CGIC will also be conducted using MMRM. The model for the analysis will 
include the fixed, categorical effects of sequence, period, and treatment. 
7. 
SAFETY ANALYSES 
All summaries of safety, including the extent of exposure to study medication, will be performed 
using the Evaluable Population. No statistical analyses are planned on safety endpoints. 
7.1. 
Study Medication Exposure and Treatment Compliance 
7.1.1. Extent of Exposure 
Time on study will be derived for each patient as: 
Time on study = Date of last dose of study drug – Date of 1st dose from lead-in phase 1 + 1. 
The extent of exposure to double-blind study drug will be derived for each treatment phase as: 
Extent of exposure = Date of last dose of double-blind study drug - Date of 1st dose of double-blind study drug + 
1. 
Time on study and extent of exposure will be descriptively summarized for each treatment 
sequence and treatment arm. 
7.1.2. Treatment Compliance 
Treatment compliance will be calculated for each treatment phase using the formula: 
Treatment Compliance =100 ( 
number of capsules received
number of capsules intended). 
The total number of tablets intended is equal to 6 times the number of days the patient spent in 
each treatment phase.  
Treatment compliance will be descriptively summarized for each treatment arm. In addition, the 
number and percent of patients with compliance < 80% or > 120% will also be presented for 
each treatment arm. 
7.2. 
Adverse Events 
Adverse events (AEs) will be collected from the day the patient gives informed consent until the 
patient leaves the study. However, if the investigator learns of any serious adverse event (SAE) 
that occurs within 30 days after the final dose of study drug, that SAE will be collected even if 
the event occurred after the patient left the study.  
TEAEs for each treatment phase reporting period are defined as reported AEs that first occurred 
or worsened after the first dose of double-blind study drug. Adverse events with an onset date on 
or after the first dose of double-blind study drug for Period 1 and before the first dose of double-
blind study drug for Period 2 will be assigned to the study drug taken during Period 1; adverse 


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events with an onset date on or after the first dose of double-blind study drug for Period 2 will be 
assigned to the study drug taken during Period 2. 
Treatment-emergent adverse events will be summarized by the number and percent of patients 
with the event. 
Summaries of TEAEs will include the number of patients with at least one TEAE for each 
treatment arm. When reporting by system organ class (SOC) and preferred term (PT), the reports 
will present the SOC in alphabetical order; while PTs within the SOC will be presented in order 
of overall decreasing frequency of occurrence in the GLWL-01 arm. A patient with multiple 
TEAEs (different PTs) coded to the same SOC will be counted only once for that SOC, but will 
be counted each time for different PTs within that SOC. A patient with separate events of the 
same PT (different start/stop dates within a treatment phase) will be counted only once in the 
frequency tables for that PT. 
An overview of all TEAEs will also be provided by treatment group using the types of AEs 
defined in the following subsections. 
7.2.1. Treatment-Emergent Adverse Events 
TEAEs will be summarized by SOC and PT for each treatment. In addition, a presentation of 
TEAE preferred terms in decreasing frequency in the GLWL-01 treatment arm will be provided.  
7.2.2. Treatment-Related Treatment-Emergent Adverse Events 
Every AE will be assessed by the investigator for its relationship to the randomly assigned study 
medication. The subset of TEAEs considered by the investigator as possibly or probably related 
to study treatment will be called treatment-related TEAEs. In addition, TEAEs that are missing 
the investigator assessment for relatedness will be considered treatment-related TEAEs. 
Treatment-related TEAEs will be summarized by SOC and PT for each treatment. 
7.2.3. Serious Treatment-Emergent Adverse Events 
Serious TEAEs and treatment-related SAEs will be summarized by SOC and PT. A separate 
listing of all SAEs will also be provided. 
7.2.4. Treatment-Emergent Adverse Events Resulting in Death 
If there are any TEAEs that result in death, a listing of all deaths will be provided.  
7.2.5. Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation 
For every AE in the eCRF, the investigator indicates whether the action taken with respect to the 
study drug was dose not changed, dose interrupted, or drug withdrawn.  
The TEAEs leading to study drug discontinuation will be summarized for each treatment arm by 
SOC and PT and by decreasing frequency in the GLWL-01 arm. A separate listing of all TEAEs 
leading to study drug discontinuation will also be provided. 


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7.2.6. Treatment-Emergent Adverse Events by Maximal Severity 
Every AE will be graded by the investigator as mild, moderate, or severe, so for each patient the 
greatest severity observed can be obtained by comparing the severity of all of a patient’s TEAEs 
that share the same SOC or PT. A table of TEAEs by maximal severity will be prepared for each 
treatment arm by SOC and PT. 
7.3. 
Clinical Laboratory Summaries 
Blood samples for hematology and serum chemistry will be collected during screening; on 
Treatment Phase Day 0 (i.e. Baseline) and Treatment Phase Day 28 of each treatment phase; and 
at a patient’s early termination visit, if applicable.  
Each laboratory parameter will be classified as low, normal or high relative to the central 
laboratory’s normal range. For each treatment group, shift tables will be generated from the pre-
dose category to the category post-dose for each laboratory parameter. The shift tables will 
present the number (percent) of patients who started in a category (low, normal, high) at baseline 
and ended in a category at each post-baseline scheduled visit and for the last assessment 
(including unscheduled and early termination assessments) for each treatment.  
Shift tables comparing baseline to the other time points in the study may be generated if 
warranted after data review. 
7.4. 
Vital Signs 
The vital signs pulse, temperature, and the mean (from triplicate measurements) sitting blood 
pressure will be assessed during screening; on Treatment Phase Day 0 (i.e. Baseline), Treatment 
Phase Day 7, and Treatment Phase Day 28 of each treatment phase; and at a patient’s early 
termination visit, if applicable.  
The number and percent of patients with any post-baseline pulse rate or mean blood pressure of 
potential clinical interest (including unscheduled and early termination assessments) will be 
summarized. Readings of potential clinical interest will be determined using the following 
criteria: 
• Pulse rate either < 50 bpm, or > 100 bpm, or a change of ≥ 15 bpm; 
• Systolic blood pressure either ≤ 90 mmHg, or ≥ 160 mmHg, or a change of ≥ 20 mmHg; 
• Diastolic blood pressure either < 50 mmHg, or ≥ 100 mmHg, or a change of ≥ 10 mmHg. 
7.5. 
Electrocardiogram Summaries 
Single 12-lead electrocardiograms (ECGs) will be assessed during screening; on Treatment 
Phase Day 0 (i.e. Baseline), Treatment Phase Day 7, and Treatment Phase Day 28 of each 
treatment phase; and at a patient’s early termination visit, if applicable. Two-hour post-dose 
ECG assessments will also be made at Baseline of each treatment phase.  
The number and percent of patients with any post-baseline Fridericia-corrected QT values of 
potential clinical interest (including unscheduled and early termination assessments) will be 
summarized. QTcF values of potential clinical interest will be determined using the following 
criteria:  


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• QTcF ≥ 480 msec, or ≥ 500 msec, or ≥ 550 msec 
• Change from baseline in QTcF ≥ 30 msec, or ≥ 60 msec. 
7.6. 
Columbia Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be listed by patient and visit.  
Only patients that show suicidal ideation and/or behavior will be displayed (i.e. if a patient’s 
answers are all ‘no’ for the CSSRS, that patient will not be listed). However, if a patient reported 
any suicidal ideation and/or behavior, all of their ideation and behavior will be displayed, even if 
not positive. 
8. 
EXPLORATORY ANALYSES 
Exploratory endpoints will be summarized separately as pharmacodynamic (i.e. AG, UAG, 
AG/UAG ratio), anthropometric (i.e. body weight, percentage fat mass, BMI, waist 
circumference), and exploratory blood chemistry (i.e. low-density lipoproteins, total cholesterol, 
and blood glucose) endpoints. 
All exploratory endpoint analyses will be performed using the Evaluable Population, using the 
same methods used for the primary efficacy endpoint. Descriptive statistics for the value and 
change from baseline will be tabulated for each time point. 
In addition, plots of the individual AG and UAG levels as well as their mean levels by treatment 
will be plotted over time. 
9. 
PHARMACOKINETIC ANALYSES 
Analyses of the pharmacokinetic (PK) parameters will be addressed in a separate PK-specific 
analysis plan.  
To investigate the potential effect of GLWL-01 on QT interval prolongation, the changes from 
baseline in QTcF values versus the plasma GLWL-01 concentration will be plotted. 
 
 


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References 
1. 
Fehnel S, Brown TM, Nelson L, Chen A, Roof E, Kim DD, Dykens EM. Development of 
the hyperphagia questionnaire for use in Prader-Willi syndrome clinical trials [poster]. In: 
ISPOR 20th Annual International Meeting; May 16-20, 2015; Philadelphia. Poster nr pp. 
A25–A25. 
2. 
Mehrotra D. A recommended analysis for 2 × 2 crossover trials with baseline 
measurements. Pharm Stat. 2014; 13(6):376-387.