Conditions: Gastroparesis Diabetes Mellitus
Keywords: diabetic gastroparesis vomiting
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 450
Healthy volunteers: no

Brief summary:
A 52-week study to compare the efficacy of relamorelin with that of placebo in participants with diabetic gastroparesis (DG) with respect to the core signs and symptoms of diabetic gastroparesis.

Detailed description:

Arms:
arm 1: Placebo injected subcutaneously twice daily for up to 52 weeks. De novo (New) participants, who did not participate in the previous relamorelin studies, began the study with a 2-week placebo run-in. arm 2: Relamorelin 10 micrograms (μg) injected subcutaneously twice daily for up to 52 weeks. De novo (New) participants, who did not participate in the previous relamorelin studies, began the study with a 2-week placebo run-in.

Interventions: intervention 1: Placebo intervention 2: Relamorelin
Intervention descriptions: intervention 1: Placebo injected subcutaneously twice daily. intervention 2: Relamorelin 10 μg injected subcutaneously twice daily.

Protocol document:
Prot_002.pdf: 
NCT03383146 
 
Study ID: RLM-MD-04 
 
 
Title: A 52-week, Randomized, Double-blind, Placebo-controlled, Phase 3 Study to Evaluate the Safety and 
Efficacy of Relamorelin in Patients with Diabetic Gastroparesis  
 
 
Protocol Amendment 3 Date: 12 February 2021 


CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
1
Title Page
Protocol Title:A 52-week, Randomized, Double-blind, Placebo-controlled, Phase 3 Studyto 
Evaluate the Safety and Efficacyof Relamorelin in Patients with Diabetic Gastroparesis
Brief Protocol Title:Diabetic Gastroparesis Study 4
Protocol Number:RLM-MD-04
Amendment Number: 3
Product:Relamorelin
Sponsor Name and Legal Registered Addresses:
Allergan Sales, LLC, 5 Giralda Farms, Madison, NJ 07940, United States
Allergan Ltd., Marlow International, Parkway, Marlow SL7 1YL, United Kingdom
Regulatory Agency Identifying Numbers:
IND: 
EudraCT: 2017-002144-33
Emergency Telephone Number: Refer to study contacts list
Serious Adverse Event ReportingEmail/Fax Number:
Allergan Medical Safety Physician: Refer to study contacts list
Sponsor Signatory:
Vice President, Clinical Development-GI
Approval Date: 12-Feb-2021 17:35:16 (GMT)


CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
2
Protocol Amendment 3 Summary of Changes
DOCUMENT HISTORY
Document
Date
Amendment 2
29 Mar2018
Amendment 1
20 Dec2017
Original Protocol
06 Oct2017
Amendment 3(29Apr2019)
Overall Rationale for Amendment3:
This summary includes changes made to Protocol RLM-MD-04from Protocol Amendment 2 
(Dated 29 Mar 2018; details provided in Section 12.19). The purpose of Protocol Amendment 3 
isto communicate changes made inresponse to recommendations from health authorities.These
changeswill not impact safety assessment of relamorelin or alter the risk-benefit ratio for study 
subjects.
The following is a summary of content-oriented changes that were made. 
Section Number
Description of Change
Rationale
Global change
Replaced “Potential Hy’s Law” 
with “Hy’s Law” (ie, deleted 
“potential throughout”
Section 1 Synopsis and 
Section4 Objectives and 
Endpoints
Removal of responder 
endpoints from list of Key 
Endpoints;
Updates to Key Objectives;
Synopsis Study Schematic 
and Section 5.1 Overall 
Design Study Schematic
Schematic updated to show 
screening starting at Week -6 
instead of Week -4
Synopsis Number of 
Participants and Section 5.2 
Participant and Study 
Completion
Increased number of screening 
participants from 4000 to 5000
Section 1 Synopsis and 
Section 5.1 Overall Design
Additional requirements for “de 
novo” participants to have had a 
history of nausea and/or at most a 
single episode of vomitingin 2 
weeks prior to Screening added 
at Screening Visit (Visit -2); 
deleted requirement for BMI.
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CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
3
Section Number
Description of Change
Rationale
Section 1 SynopsisNumber 
of Sites
Increased number of sites from 
400 to 700
Section 1 Synopsis and 
Section 6.1.2 (Inclusion 
Criteria) De Novo 
Participants
Deleted criterion for BMI 
>18.5kg/m2
Section 2 SOA
Beginning of Screening Period 
changed from Day -28 to 
Day -42 ; changed from “Up to 
14 Days” to “Up to 28 Days”
Section 2 SOA
Footnote “a” –Statement added 
that results from assessments 
done at Screening that might 
result in exclusion from the study 
are to be obtained prior to the 
endoscopy if done at the start of 
the Run-in Period.
Section 2 SOA
Added ECG assessment at 
Visit2
Section 2 SOA
Footnote referencing urine drug 
screen (ie, Footnote “j”) 
modified to specify certain 
prescribed drugs (ie, barbiturates, 
benzodiazepines, amphetamines, 
but not opioids and 
cannabinoids) should not be 
exclusionary. 
Section 2 SOA
Footnote “k” added for fasting 
glucose to be serum for all visits 
except Visits 4 and 6 (plasma).
Section 4.1 Clinical 
Hypotheses
Modified hypotheses.
Section 5.1 Overall Design
Changed requirement for delayed 
GEBT from occurring at 
Screening to occurring during the 
Run-in Period.
Section 6.1.2 De Novo 
Participants Inclusion 
Criteria
Criteria #6 –added option to use 
upper GI series with contrast to 
document absence of obstructing 
lesion; revised time of
performance from some time 
prior to Screening to some time 
prior to the Run-in Period
Section 6.2.1 Exclusion 
Criteria/Both Rollover and 
De Novo Participants
Section added for 2 new 
exclusion criteria applicable to 
both sets of participants 
including specific ECG results, 
allergy/ hypersensitivity to study 
treatment. 
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CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
4
Section Number
Description of Change
Rationale
Section 6.2.3 Exclusion 
Criteria/De Novo 
Participants
Amended Exclusion Criteria 
#12 to allow a participant with 
a positive urine drug screen at 
Screening to continue in the 
study while confirmatory 
testing is done on an aliquot of 
the original sample; added 
reference to Section 6.4
AddedExclusion Criteria #25 
(hypersensitivity to study 
treatments and their excipients) 
and #26 (ECG results obtained 
at baseline that would exclude 
a participant)
Section 6.4 Screen Failures
Added option for the sponsor to 
permit a participant with a 
positive urine drug screen at 
Screening to continue in the 
Screening Period while 
confirmatory urine drug screen 
testing by a more specific 
method is carried on an aliquot of 
the original sample.
Section 7.1Treatments 
Administered
Clarified that the first dose of 
study treatment is to be 
administered within 
approximately30 minutes before
the morning meal and the second 
daily dose is to be administered 
approximately30 minutes before
the evening meal.
Deleted option for investigator to 
contact sponsor if the participant 
could not inject study treatment 
into abdomen.
Section 7.4 
Blinding/Masking
Unblinding procedures modified; 
requirement of investigator to 
notify sponsor prior to 
unblinding modified to 
encouraging the investigator to 
notify the sponsor prior to 
unblinding, but requiring 
notification within 24 hours after 
breaking the blind.
Section 7.7.1 Prohibited 
Treatments and Washout 
Before the Study
SLGT-1 added to same rules for 
SGLT-2.  Addition of details to 
the requirement of prohibiting 
SGLT-1 and SGLT-2 inhibitors.
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CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
5
Section Number
Description of Change
Rationale
Section 7.7.1, Table 7-2 
Prohibited Medications and 
Washout Requirements
Amended information 
regarding SGLT-2inhibitors as 
noted above and by adding 
SLGT-1 to same drug 
class/treatment as SGLT-2, 
rearranged rows by washout 
period, added tramadol as an 
example of opioid.
Pro-motility agents, 
anticholinergics, anti-emetics, 
amyline analogue, 5HT4 
agonists, and glucagon-like 
peptide-1 –added washout 
requirements for de novo 
participants
Updated description of anti-
emetics.
Added row for 5HT4 agonists.
Amended washout periodfor 
opioids from “10 days prior to 
the start of the Run-in Period” 
to Not applicable since use of 
opioids is not allowed and 
referenced exclusion criteria 
#12 and #13. 
Section 7.7.3 Rescue 
Medicine
Specified that the day prior to 
and day of clinic visits are 
“during the Treatment Period”.
Deleted antihistamines as an 
example of an anti-emetic 
drug.
Revised to require investigator 
to contact (ie, “should contact) 
sponsor if participant requires 
anti-emetic more than 1 
day/week or once weekly 
repeatedly instead of making it 
optional for investigator to 
contact (ie, “should consider 
contacting).
Section 8 
Discontinuation/Withdrawal 
Criteria
Deleted “non-compliance with 
study treatment” as a criterion
Section 8.1.1 Temporary 
Discontinuation
Additional criteria added for 
when the investigator should 
contact the sponsor.
Approval Date: 12-Feb-2021 17:35:16 (GMT)


CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
6
Section Number
Description of Change
Rationale
Section 9.1.1 Key Efficacy 
Assessment -DGSSD
Added statement detailing 
when participants would be 
reporting their symptoms in the 
DGSSD.
Deleted description on 
vomiting frequency and how 
vomiting will be calculated.
Section 9.2.1 Time Period 
and Frequency for 
Collecting AE and SAE 
Information
Specified that medical 
occurrences that begin before the 
start of study treatment but after 
obtaining IC will be recorded in 
the AE section of the eCRF and 
will be considered pretreatment 
AEs (instead of being recorded 
on the Medical History/Current 
Medical Conditions section of 
the eCRF).
Section 9.2.7.1 Hy’s Law
Clarified reporting procedures 
for Hy’s Law cases
Section 9.2.7.2 Inadequate 
Control of Diabetes: 
Hyperglycemia and 
Hypoglycemia
Added the phrase “Inadequate 
Control of Diabetes” to section 
title
Section 9.2.8 Medication 
Errors
Specified 10 µg BID or 
20µg/day as the maximum 
recommended dose.
Deleted statement referencing a 
dose of greater than 150 µg BID 
to be considered an overdose. 
Section 10.2 Populations for 
Analyses/Table 10-1 
Analysis Populations
Specified that the mITT 
Population is a subset of all 
randomizedparticipants.
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CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
7
Section Number
Description of Change
Rationale
Section 10.3.1 Key 
Statistical 
Methodology/Table 10-2 
Statistical Methodology
Replaced Responder analysis 
with CFB MMRM methodology 
and description;deleted CFB 
ANCOVA methodology and 
description
Section 10.3.2.1 Key 
Endpoints/Table 10-3 Key 
Endpoints
Updated to only include CFB to 
Week 12 in weekly DGSSS and 
CFB to Week 52 in weekly 
average DGSSS
Section10.3.2.2 Missing 
Data
Deleted original text and 
replaced with reference to SAP
Section 10.3.5 Interim 
Analyses
Replaced the “Non-applicable” 
statement with a description of a 
DSMB process that will be used 
to review interim safety data.
Section 12.2 Appendix 2 
Clinical Laboratory Tests, 
Table 12-1
Footnote added for fasting blood 
glucose to be serum at all visits 
except for Visits 4 & 6
Section 12.3 Appendix 3:  
Study Governance 
Considerations
Headings added for subsections 
Section 12.3.3 Informed 
Consent Process
Statement added that written 
documentation must be obtained 
in accordance with relevant 
country and local privacy 
requirements
Section 12.3.5 Data Quality 
Assurance
Revised from requirement of 
investigator retaining records for 
15 years after study completion 
to retaining “as stated in the 
clinical trial agreement”.
Section 12.3.8 Publication 
Policy
Added statement that the results 
of the study may be published or 
presented at scientific meetings.
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CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
8
Section Number
Description of Change
Rationale
Section 12.4 Appendix 4 
AE Definitions and 
Procedures for Recording, 
Evaluating, Follow-up and 
Reporting
Updated procedures for 
reporting AESIs.
Identified specific AESIs (ie, 
Hy’s law cases, inadequate 
control of diabetes:  
hyperglycemiaand 
hypoglycemia, and MACE).
Specified that DG symptoms 
will be captured in the DGSSS 
and not the CRF
Section 12.5 Appendix 5 
Contraceptive Guidance and 
Collection of Pregnancy 
Information
Moved acceptable methods of 
contraception from text to 
table.
Section 12.8, Appendix 8 
Standard Discontinuation 
Criteria
Removed criteria for non-
compliance
Section 12.9, Appendix 9 
Study Tabular Summary
Changed trial length from 52 
to 54 weeks
Changed number of 
participants to be screened 
from 4000 to 5000
Additional administrative edits were also made, but not specifically noted (eg, corrected spelling, 
punctuation, grammar, abbreviation, andstyle errors)including global edits required for 
consistency.
Approval Date: 12-Feb-2021 17:35:16 (GMT)


CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
9
Table of Contents
Title Page 
...........................................................................................................................1
Protocol Amendment 3 Summary of Changes................................................................................2
Table of Contents...........................................................................................................................9
List of Tables
.........................................................................................................................13
List of Figures
.........................................................................................................................13
1
Synopsis..........................................................................................................14
2
Schedule of Activities (SoA)..........................................................................18
3
Introduction.....................................................................................................22
3.1
Study Rationale...............................................................................................23
3.2
Background.....................................................................................................24
3.3
Benefit/Risk Assessment.................................................................................26
4
Objectives and Endpoints...............................................................................26
4.1
Clinical Hypotheses........................................................................................27
5
Study Design...................................................................................................27
5.1
Overall Design................................................................................................27
5.2
Participant and Study Completion..................................................................29
5.3
End of Study Definition..................................................................................29
5.4
Scientific Rationale for Study Design.............................................................30
5.5
Justification for Dose......................................................................................30
6
Study Population.............................................................................................31
6.1
Inclusion Criteria............................................................................................31
6.1.1
Rollover Participants.......................................................................................31
6.1.2
De Novo Participants......................................................................................32
6.2
Exclusion Criteria...........................................................................................33
6.2.1
Both Rollover and De Novo Participants........................................................33
6.2.2
Rollover Participants.......................................................................................33
6.2.3
De Novo Participants......................................................................................33
6.3
Lifestyle Restrictions......................................................................................35
6.4
Screen Failures................................................................................................35
7
Treatments.......................................................................................................36
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CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
10
7.1
Treatments Administered................................................................................36
7.1.1
Study Supplies................................................................................................38
7.2
Dose Modification..........................................................................................38
7.3
Method of Treatment Assignment...................................................................38
7.4
Blinding/Masking...........................................................................................38
7.5
Preparation/Handling/Storage/Accountability................................................39
7.6
Treatment Compliance....................................................................................39
7.7
Concomitant Therapy......................................................................................40
7.7.1
Prohibited Treatments and Washout Before the Study...................................40
7.7.2
Permitted Treatments......................................................................................41
7.7.3
Rescue Medicine.............................................................................................42
7.8
Treatment after the End of the Study..............................................................42
8
Discontinuation/Withdrawal Criteria..............................................................42
8.1
Discontinuation of Study Treatment...............................................................43
8.1.1
Temporary Discontinuation............................................................................44
8.2
Withdrawal from the Study.............................................................................44
8.3
Lost to Follow Up...........................................................................................45
9
Study Assessments and Procedures................................................................45
9.1
Efficacy Assessments......................................................................................46
9.1.1
Key Efficacy Assessment -DGSSD...............................................................46
9.2
Adverse Events...............................................................................................49
9.2.1
Time Period and Frequency for Collecting 
AE and SAE Information...........49
9.2.2
Method of Detecting AEs and SAEs...............................................................50
9.2.3
Follow-up of AEs and SAEs...........................................................................50
9.2.4
Regulatory Reporting Requirements for SAEs...............................................50
9.2.5
Pregnancy........................................................................................................50
9.2.6
Medical Device Incidents (Including Malfunctions)......................................51
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CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
11
9.2.6.1
Time Period for Detecting Medical Device Incidents....................................51
9.2.6.2
Follow-up of Medical Device Incidents.........................................................51
9.2.6.3
Prompt Reporting of Medical Device Incidents to Sponsor...........................52
9.2.6.4
Regulatory Reporting Requirements for Medical Device Incidents...............52
9.2.7
Adverse Events of Special Interest.................................................................52
9.2.7.1
Hy’s Law.........................................................................................................52
9.2.7.2
Inadequate Control of Diabetes:  Hyperglycemia and Hypoglycemia...........53
9.2.7.3
Major Adverse Cardiovascular Events............................................................53
9.2.8
Medication Errors...........................................................................................54
9.3
Treatment of Overdose....................................................................................54
9.4
Safety Assessments.........................................................................................55
9.4.1
Physical Examinations....................................................................................55
9.4.2
Vital Signs.......................................................................................................55
9.4.3
Electrocardiograms.........................................................................................55
9.4.4
Clinical Safety Laboratory Assessments.........................................................56
9.4.5
Self-monitoring of Blood Glucose..................................................................56
9.5
Pharmacokinetics............................................................................................57
9.6
Pharmacodynamics.........................................................................................57
9.7
Genetics...........................................................................................................57
9.8
Biomarkers......................................................................................................57
10
Statistical Considerations................................................................................59
10.1
Sample Size Determination.............................................................................59
10.2
Populations for Analyses.................................................................................59
10.3
Statistical Analyses.........................................................................................59
10.3.1
Key Statistical Methodology...........................................................................59
10.3.2
Efficacy Analyses............................................................................................60
10.3.2.1
Key Endpoints.................................................................................................60
10.3.2.2
MissingData...................................................................................................61
10.3.3
Safety Analyses...............................................................................................61
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Protocol RLM-MD-04, Amendment 3
Relamorelin
12
10.3.5
Interim Analyses.............................................................................................61
11
References.......................................................................................................62
12
Appendices......................................................................................................64
12.1
Appendix 1: Abbreviations and Trademarks...................................................65
12.2
Appendix2: Clinical Laboratory T
ests...........................................................69
12.3
Appendix 3: Study Governance Considerations.............................................71
12.3.1
Regulatory and Ethical Considerations...........................................................71
12.3.2
Financial Disclosure........................................................................................71
12.3.3
Informed Consent Process..............................................................................72
12.3.4
Data Protection................................................................................................74
12.3.5
Data Quality Assurance...................................................................................74
12.3.6 
Source Documents..........................................................................................75
12.3.7
Study and Site Closure....................................................................................75
12.3.8
Publication Policy...........................................................................................75
12.4
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting............................................................77
12.5
Appendix5: Contraceptive Guidance and Collection of Pregnancy 
Information.....................................................................................................84
12.6
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments..88
12.7
Appendix 7: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................89
12.8
Appendix 8: Standard Discontinuation Criteria..............................................91
12.9
Appendix 9: Study T
abular Summary.............................................................92
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CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
13
List of Tables
Table 7–1
Study Treatment Details..................................................................................37
Table 7–2
Prohibited Medications and Washout Requirements......................................41
Table 10–1
Analysis Populations.......................................................................................59
Table 10–2
Statistical Methodology..................................................................................60
Table 10–3
Key Endpoints.................................................................................................60
Table 12–1
Protocol-Required Safety Laboratory Assessments........................................70
List of Figures
Figure 5-1
RLM-MD-04 Study Schematic.......................................................................28
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CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
14
1 Synopsis
Protocol Title:A 52-week, Randomized, Double-blind, Placebo-controlled, Phase 3 Studyto 
Evaluate the Safety and Efficacyof Relamorelin in Patients with Diabetic Gastroparesis
BriefTitle:Diabetic Gastroparesis Study 4
Study Rationale:Previous non-clinical and Phase 1 studies have shown relamorelin to have a 
potent prokinetic effect on the stomach, accelerating gastric emptying (GE) in both healthy 
volunteers and patients with diabetic gastroparesis (DG). 
Gastroparesis (GP) is a disorder characterized by signs and symptoms of nausea, abdominal pain, 
postprandial fullness, bloating, vomiting, and early satiety along with delayed GE, such that 
movement of food from the stomach to the small intestine takes longer than normal and occurs 
with unpredictable timing. Diabetes mellitus, either type 1 or 2 (T1DM or T2DM), is considered 
to be the most common identifiable cause of GP
. This complication is a result of chronically 
elevated blood glucose levels, which are known to damage nerve structure and function. DG 
complicates management of blood glucose for both T1DM and T2DM patients due to 
carbohydrates being delivered to and therefore absorbed from the small intestine at variable 
times after ingestion. As a result, diabetic patients with DG often have poorly controlled 
diabetes, frequently with alternating hypo-and hyperglycemia, especially if treated with insulin.
In Phase 2 studies, thepharmacodynamic effect of relamorelin was confirmed in larger numbers 
of participants with DG, and in addition, beneficial effects on the symptoms of DG were 
observed. Safety and tolerability were shown at therapeutic doses,including the 10 μg twice 
daily (BID)dose to be studied in Phase 3 studies, supporting the decision to obtain confirmatory 
evidence of safety and efficacyof relamorelin in Phase 3, and specifically in studyRLM-MD-04.
A
 significant unmet medical need exists for a safe and effective treatment of patients with DG 
whose quality of life is impacted by their disease and for whom the current standard of care is 
suboptimal; therefore, the sponsor is performing this study to further the development of 
relamorelin for the treatment of DG.
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CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
15
Objectivesand Endpoints:
Key Objectives
Key Endpoints
To comparethe efficacy of relamorelinwith that of 
placebo in participants with DGwith respect to a 
composite of the following core signs and 
symptoms of DG:
o
Nausea
o
Abdominal pain
o
Postprandial fullness
o
Bloating
Change from baseline to Week 12 in the weekly 
DGSSS
Change from baseline to Week 52 in weekly 
average DGSSS
To compare the safety of relamorelin with that of 
placebo in participants with DG
AEs, clinical laboratory values, vital signs, ECGs, 
HbA1c,and anti-relamorelin antibodies
Overall Study Design:
Global, multicenter,randomized, double-blind, placebo-controlled, parallel-group
Treatment Group: Relamorelin10 μgor placebosubcutaneously (SC) twice daily (BID)
Study Duration: 52-weekTreatment Period
Participants who meet study entry and randomization criteria will be randomized in a 
2:1ratioto blinded treatment with relamorelin 10 µg or placebo, and willuseanelectronic 
hand-held device for reporting of their symptoms,
ompliance, and use 
of rescue medication.
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CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
16
Study Schematic:
Number of Participants:
Planned enrollment for this study is 600 participants assigned to study treatment (400 to 
relamorelin and 200 to placebo). A
 total of 300 participants are expected to complete the study 
(200 relamorelin- and 100 placebo-treated participants).
Approximately 5000 participants will be screened in lead-in Studies RLM-MD-01 and 
RLM-MD-02. Participants who do not meet certain randomization criteria may enter this study 
directly if they meet enrollment criteria defined below. 
Study Population:
Two different groups of participants may enter the study:
1. Participants who met all Screening and Run-in Period criteria in lead-in Study 
RLM-MD-01 or lead-in Study RLM-MD-02 (including compliance with dosing and 
data entry into the Diabetic Gastroparesis Symptom Severity Diary [DGSSD] during 
the lead-in study Run-in Period), but were not randomization-eligible at the end of the 
lead-in study Run-in Period, are eligible for randomization in Study RLM-MD-04 if:
They had no vomiting episodes recorded in the DGSSD and had an average daily 
DGSSS ≥ 12 at the end of the lead-in study Run-in Period.
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CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
17
OR
They hadvomiting episodes recorded in the DGSSD but hadanaverage daily 
DGSSS of ≥12and < 16at the end of the lead-in study Run-in Period. 
In the current study, these “rollover participants”will enter the studyat Visit 1 
(Randomization); they will not undergo Screening (Visit –2) or Run-in Visit (Visit –1)
procedures.
2. Patients who undergo screening and run-in proceduresin StudyRLM-MD-04are “de 
novo participants”. T
o be eligible for randomization in the current study, de novo 
participants mustmeet all Screening and Run-in Period criteriafor Study RLM-MD-04, 
including:
At the ScreeningVisit(Visit –2):
Maleor female aged 18 years and older; 
T1DM or T2DM with controlled and stable bloodglucose levels and HbA1c 
≤11%; 
Symptoms suggestive of DG for at least 3 months(one of which must be nausea), 
withmechanical obstruction of the gastrointestinal (GI) tract as the cause of 
symptoms havingbeen ruled out; 
History of nausea and/or at most a single episode of vomiting in the 2 weeks prior 
to Screening (Visit -2), as ascertained by participant history
At the End of the Run-in Period:
Evidence of compliance during the Run-in Period with both the useofthe 
electronic hand-held device for entry of data and with twice daily SC injections 
ofthestudy treatment; 
No treatment with GI promotility agents during the Run-in Period;  
A
 score of ≥12for the average of the daily DGSSS measured during the Run-in 
Period.
Number of Sites: 
Approximately 700sites globally(the combined number of sitesfromStudiesRLM-MD-01 and 
RLM-MD-02).
Approval Date: 12-Feb-2021 17:35:16 (GMT)


CONFIDENTIAL
Protocol RLM-MD-04, Amendment 3
Relamorelin
18
2 Schedule of Activities(SoA)
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3 Introduction
Relamorelin (also known as RM-131) is a novel, potent, and selective synthetic penta-peptide 
ghrelin analogue, which is being developed for treatment of diabetic gastroparesis (DG). 
Ghrelin, a 28 amino-acidpeptide, is produced predominantly by specialized cells of the stomach 
and pancreas, and has been demonstrated to be a central modulator of energy homeostasis. It is 
the natural ligand for the Growth Hormone Secretagogue 1 α (GHS1α) receptor, a potential 
target for treatment of clinical conditions associated with impaired gastric motility and energy 
balance. Administration of ghrelin has been shown to promote gastric motility in mice, rats, dogs 
and humans (Dornonville et al, 2004; Trudel et al, 2003; and Murray et al, 2005). It can increase 
body weight, attributed to a combination of enhanced food intake, increased gastric emptying 
(GE), and increased food assimilation, coupled with a transient increase in growth hormone 
(GH), which promotes nutrient incorporation into tissues.
Relamorelin has similar characteristics to native ghrelin but with enhanced efficacy, plasma 
stability, and circulating half-life. As a ghrelin mimetic, it acts as a potent prokinetic agent, as 
evidenced by significant effects on GE as well as effects on overall colonic transit (Acosta et al, 
2015, Acosta et al, 2016). 
Gastroparesis (GP) is a disorder characterizedby delayed GE, such that movement of food from 
the stomach to the small intestine is delayed. The pathophysiology of GP has not been fully 
elucidated but seems to involve abnormalities in the autonomic nervous system (vagus nerve), 
smooth muscle cells, enteric neurons, and interstitial cells of Cajal; in DG, change in the type of 
macrophages in the gastric musculature suggest a role for inflammation as a cause of delayed 
GE. 
Diabetes mellitus, either type 1 or 2 (T1DMor T2DM, respectively), is consideredto be the most 
common, specifically identifiable cause of GP. This complication is a result of chronically 
elevated blood glucose levels, which are known to damage nerve structure in general,and the 
vagus nerve in particular, and negatively affect function (Parkman et al, 2004). 
DG is a chronic condition that requires prolonged treatment. Core signs and symptoms of DG are 
nausea, abdominal pain, postprandial fullness, bloating,vomiting, and early satiety (a feeling of 
fullness after eating just a few bites) (Camilleri et al, 2013). These symptoms can be debilitating 
and, when uncontrolled, havea significant negative impact on patient quality of life and 
functioning, including work productivity (Camilleri et al, 2011, Parkman et al, 2011). Serious 
adverse sequelae of DG include: potentially life-threatening dehydration due to persistent 
vomiting, gastroesophageal reflux disease (GERD) that can advance to esophagitis, formation of 
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bezoars, difficulty managing blood glucose levels, and malnutrition due to poor absorption of 
nutrients or a low-calorie intake (U.S. Department of Health and Human Services, 2012). Aside 
from the impact on patients, these events often lead to hospitalization (Koch et al, 2016), 
resulting in a high economic burden for health care systems. 
DGcomplicates managementof blood glucose for both T1DMand T2DM patients due to 
carbohydrates being delivered to and therefore absorbed from the small intestine at unpredictable 
times (Rayner et al, 2001). As a result, diabetic patients with DG often have poorly controlled 
diabetes, frequently with alternating hypo-and hyperglycemia, especially if treated with insulin. 
Little data on the incidence and prevalence of GP are available; however, an older epidemiology 
study of diagnosed GP (defined as typical symptoms plus confirmed delayed GE by 
scintigraphy) showedprevalence of 24.3 per 100,000 inhabitants and incidence of 6.3 per 
100,000 persons per year in Olmstead County, MN from 1996 to 2006 (Junget al,2008). This 
study reported that age-adjusted prevalence of GP was approximately 4 times greater for women 
than men (37.8 versus 9.6 cases per 100,000 persons). It has been reported that 30to 50% of 
diabetic patients have delayed GE, while the prevalence of the specific symptoms of GP (nausea 
and vomiting) is lower, with approximately 10% of patients with diabetes being affected 
(HopkinsMedicine.org, 2013). According to Bharucha(2015), in a restricted community-based 
study of GP in diabetes mellitus, the average cumulative incidence of symptoms and delayed GE 
over 10 years was higher in T1DM (5%) than in T2DM (1%) and controls (1%). It is expected 
that the incidence of DG will increase worldwide in proportion to the increase in T2DM due to 
increasing obesity
.
3.1 Study Rationale
Previous non-clinical and Phase 1 studies have shown relamorelin to have a potent prokinetic 
effect on the stomach, accelerating GE in both healthy volunteers and patients with DG. 
GP is a disorder characterized by signs and symptoms of nausea, abdominal pain, postprandial 
fullness, bloating, vomiting, and early satiety along with delayed gastric emptying (GE), such 
that movement of food from the stomach to the small intestine takes longer than normal and 
occurs withunpredictable timing. T1DM or T2DMis considered to be the most common 
identifiable cause of GP
. This complication is a result of chronically elevated blood glucose 
levels, which are known to damage nerve structure and function. DG complicates management 
of blood glucose for both T1DM and T2DM patients due to carbohydrates being delivered to and 
therefore absorbed from the small intestine at variable times after ingestion. As a result, diabetic 
patients with DG often have poorly controlled diabetes, frequently with alternating hypo-and 
hyperglycemia, especially if treated with insulin.
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In Phase 2 studies, the pharmacodynamic effect of relamorelin was confirmed in larger numbers 
of participants with DG, and in addition, beneficial effects on the symptoms of DG were 
observed. Safety and tolerability were shown at therapeutic doses,including the 10 μg twice 
daily (BID)dose to be studied in Phase 3 studies, supporting the decision to obtain confirmatory 
evidence of safety and efficacy of relamorelin in Phase 3, including supportive evidence from
Study RLM-MD-04.
A
 significant unmet medical need exists for a safe and effective treatment of patients with DG
whose quality of life is impacted by their disease and for whom the current standard of care is 
suboptimal; therefore, the sponsor isperforming this study to further the development of 
relamorelin for the treatment of DG, specifically to assess the effect of long-term treatment in a 
population with less vomiting and/or lower baseline Diabetic Gastroparesis Symptom Severity 
Score (DGSSS)than the population enrolled in the pivotal efficacy studies, RLM-MD-01 and 
RLM-MD-02.
3.2 Background
Relamorelin is being developed for the treatment of patients with DG to address the existing
unmet need for an effective and safe/tolerable treatment, attested to by the FDA
’s granting of 
fast-track designation to relamorelin for the treatment of DG in adults.It is a member of an 
established class of compounds, ghrelin agonists, but if granted regulatory approval, will be the 
first member of this class to attain marketing approval.
Inclinical studies to date, 466 participantswithT1DM or T2DM with DG have been exposed to 
relamorelin at doses up to 100 μg administered twice daily by subcutaneous (SC) injection for 
12-weeks. 
In a randomized, placebo-controlled, multiple-dose Phase 2a study (RM-131-004), participants
with T1DMand T2DM and DG received 28 days of double-blind treatment with relamorelin. GE 
was accelerated and compared to placebo, relamorelin 10 µg BID significantly decreased the 
vomiting severity score and mean number of weekly vomiting episodes in participantswith 
vomiting at baselineand produced improvement in the 4 individual DG symptoms of nausea, 
abdominal pain, bloating and early satiety as well as significant improvement in the composite 
endpoint of the 4 symptoms (p=0.043). The safety and tolerability profile of relamorelin in 
Study RM-131-004 was generally good.
The results in Study RM-131-004 helped the sponsor select the target patientpopulation for 
enrollment in the Phase 2b Study RM-131-009, DG patientswith vomiting at baseline, and 
encouraged assessment of a wider range of relamorelin doses.
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Study RM-131-009 was a randomized, double-blind, placebo-controlled, stratified, multiple 
dose, multi-national study with 10 µg BID, 30 µg BID,and 100 µg BID doses of relamorelin. A
 
total of 393 participants withT1DM or T2DM, who had both delayed GE and moderate to severe 
symptoms of GP were enrolled and treated. The Phase 2b study confirmed a statistically 
significant effect of relamorelin over placebo on GE for the 10µg and 30µg doses. Vomiting 
episodes were reduced from baseline to Week 12 by approximately 75% in all relamorelin dose 
groups; however, there was also a strong, previously unobserved placebo effect on vomiting 
frequency (reduction of approximately 70%) that precluded statistical significance of the 
relamorelineffectthat was observed. Results for the key secondary endpoint, a composite score 
of 4 DG symptoms (nausea, abdominal pain, bloating,and early satiety) showed benefit of 
treatment with relamorelin compared to placebo although the difference was not statistically 
significant; the same was true for an exploratory endpoint, a composite score of 4 DG symptoms 
that included postprandial fullness instead of early satiety. 
Relamorelin was generally safe and well toleratedamong patients with T1DM or T2DMand DG. 
There were more reports of diarrhea and hyperglycemia-related events on relamorelin compared 
to placebo; hypoglycemia was infrequently reported (1.2% incidence in the placebo and 
relamorelin 100 μg groups only).Twenty-three serious adverse events (SAEs)were reported in 
the 289 participantstreated withthe 3 doses ofrelamorelin and 8 in the 104 participants treated 
with placebo. The number and characteristics of the reported SAEs reflected the advanced 
underlying disease state of this DG population with long-standing T1DM or T2DM and other 
common co-morbidities and only 2of the SAEs(cardiac failure congestive and diabetes mellitus 
inadequate control) were assessed by the investigator as possibly related to study treatment, both 
in the 100-µg treatment group.Threeadverseevents(AEs)of diabetic ketoacidosis were 
reported, one event on each relamorelin dose. A
 total of 20 relamorelin-treated participantsand 3 
placebo-treated participantsdiscontinued study treatment because of a treatment-emergent AE; 
only 3 in the relamorelin 10 µg BID group.
With respect to laboratory findings, in some participants, glycemic control may have been
negatively affected by the introduction of relamorelin. There were trends in increasing 
hemoglobin A1c (HbA1c) values afterthe initiation of relamorelin, whichincreased slightlyafter 
approximately 8 weeks, and dose-related trends in fasting hyperglycemia. Otherwise, no 
clinically relevant abnormalities were seen for other laboratory tests, including liver function 
tests, electrocardiograms(ECGs), physical examination findings, and injection site reactions; 
anti-drug antibodies (ADAs) were not found.
A
 detailed description of the chemistry, pharmacology
, efficacy
, and safety of relamorelin is 
provided in the investigator’s brochure(Relamorelin Investigator’s Brochure).
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3.3 Benefit/Risk Assessment
Based on information about relamorelin obtained to date, the benefits of study participation are 
expected to include accelerated GEand clinically meaningful improvement in the symptoms of 
DG, including nausea, abdominal pain, postprandial fullness, bloating, vomitingfrequency, early 
satiety, and vomiting severity
. 
A
 potential risk of treatment is worsening of glycemic control, 
including the possibility of diabetic ketoacidosis occurring. However, preventive measures, 
including special laboratory assessments to allow early recognition by investigators and 
participants of rising glucose levels, are being included in this protocol so that early remedial 
action (eg,adjustment of medication and diet) may be taken to minimize increase in glucose 
levels; this might increase the incidence of hypoglycemic reactions, especially in participants 
with T1DM. SeeSection5, Study Design for details of study procedures, dose, and study design 
justification.
More detailed information about the known and expected benefits and risks and reasonably
expected AEs associated with relamorelin treatment may be foundin the investigator’s brochure 
(Relamorelin Investigator’s Brochure); information about the investigational directions for use 
for the pen injector, the device that will be used to administerstudy treatmentare also provided.
4 Objectives and Endpoints
Key Objectives
Key Endpoints
To comparethe efficacy of relamorelinwith that of 
placebo in participants with DGwith respect to a 
composite of the following core signs and 
symptoms of DG:
o
Nausea
o
Abdominal pain
o
Postprandial fullness
o
Bloating
Change from baseline to Week 12 in the weekly 
DGSSS
Change from baseline to Week 52 in weekly 
average DGSSS
To compare the safety of relamorelin with that of 
placebo in participants with DG
AEs, clinical laboratory values, vital signs, ECGs, 
HbA1c,and anti-relamorelin antibodies
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4.1 Clinical Hypotheses
The clinical hypotheses are:
DG participants receiving relamorelin compared to DG participants receiving placebo will 
experience greater improvementin DGSSSas measured by:
The change from baseline to Week 12 weekly DGSSS, and
The change from baseline to Week 52 weekly average DGSSS(defined as the average 
of the 4 weekly DGSSSfromthe 4 weeks prior to the Week 52 visit).
Baseline is defined as the average of the 2 average DGSSS from the 2-week placebo Run-in 
Period.
5 Study Design
5.1 OverallDesign
Global, multicenter, randomized, double-blind, placebo-controlled, parallel-group
Treatment Groups: Relamorelin 10 μgand placebo;BID, SC 
Study Duration: 52-weekTreatment Period. 
See Figure 5-1for a Study Schematic.
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Figure 5-1
RLM-MD-04 Study Schematic
 
Study Population:
Two different groups of participants may enter into the study:
1. Participants who met all Screening and Run-in Period criteria in lead-in Study RLM-MD-
01 or lead-in Study RLM-MD-02 (including compliance with dosing and data entry into 
the DGSSD during the lead-in study Run-in Period), but were not randomization-eligible 
at the end of the lead-in study Run-in Period, are eligible for randomization in Study 
RLM-MD-04 if:
They had no vomiting episodes recorded in the DGSSD and had an average daily 
DGSSS ≥ 12 at the end of the lead-in study Run-in Period.
OR 
They had vomiting episodes recorded in the DGSSD but had an average daily 
DGSSS of ≥12 and < 16 at the end of the lead-in study Run-in Period. 
In the current study, these “rollover participants” will enter the study at Visit 1 
(Randomization); they will not undergo Screening (Visit –2) or the Run-in Visit (Visit –1) 
procedures
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2. Patientswho undergo screening and run-in procedures in StudyRLM-MD-04are 
“denovo participants”. T
o be eligible for randomization in the current study, de novo 
participants mustmeet all Screening and Run-in Period criteriafor Study RLM-MD-04, 
including:
a. At Screening, be maleor female age 18 years and older; T1DM or T2DM with 
controlled and stable blood glucose levels and HbA1c ≤11%; symptoms 
suggestive of DG for at least 3 months(one of which must be nausea), with 
mechanical obstruction of the GI tract as the cause of symptoms havingbeen 
ruled out.
b. History of nausea and/or at most a single episode of vomiting in the 2 weeks 
prior to Screening (Visit -2), as ascertained by participant history
c. During the Run-in Period, delayed GE by gastric emptying breath test (GEBT)
d. After Run-in Period: Evidence of compliance during the Run-in Period with the 
use of the electronic hand-held device for entry of data,with twice daily SC 
injections of the study treatment, and no treatment with GI promotility agents; a 
score of ≥12for the average of the daily DGSSS measured during the Run-in 
Period.
For studies conducted at US (IND) sites and non-US (non-IND) sites, data from IND and 
non-IND study sites will be pooled together for analysis.
5.2 Participantand Study Completion
Approximately 5000participants will be screened in lead-in Studies RLM-MD-01 andRLM-
MD-02. Certain participants who were not eligible for randomizationat the end of thelead-in 
studyRun-in Period(rollover participants)may enter this study(see Section 5.1for rollover 
participant eligibility criteria).
In addition, participantswho undergo Screening and Run-in Visit procedureswill be eligible for 
randomization if they meet all inclusion/exclusioncriteriafor the current study(see 
Sections6.1.2and 6.2.3for de novo participant eligibility criteria). 
The goal is to achieve 600 participants assigned to study treatment(400 to relamorelin and 
200to placebo). 
A
 total of 300participants are expected to complete the study(200 treated with 
relamorelin and 100 withplacebo). See Section10.1for details on sample size determination.
5.3 Endof StudyDefinition
The end of the study is defined as the date of the last visit of the last participant in the study.
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A
 participant is considered to have completed the study if he/she has completedat least 364days 
of treatment, and thelast visit(Visit 7).Independent of the end of study definition, all laboratory 
tests with values considered clinically significantly abnormal during participation in the study or 
within 30daysafter the last dose of study treatment should be repeated until the values return to 
normal or baselineor are no longer considered clinically significant by the investigator or 
medical safety physician (MSP).
5.4 Scientific Rationale forStudy Design
The sponsor has designed this randomized, double-blind, placebo-controlled, parallel-group
study to follow regulatoryrecommendations for conduct of Phase 3 therapeutic confirmatory 
studies, specifically the ICH Harmonized Tripartite Guideline E8 (General Considerations for 
Clinical Trials, Current Step 4 version dated 20 July 2000) and Guideline E10 (Choice of Control 
Group and Related Issues in Clinical Trials, Current Step 4 version dated 17 July 1997). The 
study also has been designed to comply with recommendations made by the US FDA, Center for 
Drug Evaluation and Research (CDER) in the Draft Guidance for Industry, Gastroparesis: 
Clinical Evaluation of Drugs for Treatment, July 2015, including those for the minimum duration 
of studies to show efficacy (at least 12 weeks) and for inclusion of a long-term placebo-
controlled safety study (12 months, with appropriate pre-specified provisions for rescue 
medications)as part of the development plan.
Several design features have been incorporated in the current study in an effort to minimize bias, 
including double-blind designand random assignment of participants, helping to ensure that both 
known and unknown risk factors are distributed evenly between treatment groups.The use of a 
placebo control permits prospective comparison between the relamorelingroup and the control 
group.
5.5 Justification for Dose
Study RM-131-009 was a 12-week Phase 2b, randomized, double-blind, placebo-controlled, 
parallel group study to evaluate the safety and efficacy of relamorelinin diabetic participants 
with moderate to severe DG. The doses included within the study were 10 µg BID, 30 µg BID, 
and 100 µg BID.In general, all doses tested within RM-131-009 appeared to demonstrate 
meaningful reductions in overall DG symptom scores including vomiting episodes, with 
acceptable safety and tolerability. The frequency of vomiting episodes was reduced from baseline 
over the 12-week treatment period to a similar extent for participants who received the3doses of 
relamorelin testedand placebo. Based upon the observed dose response of change-from-baseline 
symptom scores collecteddaily over the course of 12 weeksusing the DGSSD, the 30 µg BID, 
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and 100µg BID doses demonstrated apparent maximal symptom score improvements, while the 
10 µg BID dose achieved near maximal improvements. Of note, the twice-a-day regimen of 
relamorelin appears to be necessary for effective symptom relief;the 10µg once daily (QD)
relamorelindid not demonstrate significant improvement in symptom relief compared to placebo 
after 28 days of dosing in StudyRM-131-004.
Review of the safety laboratory data collected in RM-131-009 revealed an apparent dose-related 
increase in HbA1c values. Although the variability in HbA1c response was high across all 
treatments, the 30 µg BID and 100 µg BID doses demonstrated apparent maximal changes in 
HbA1c values, while the 10 µg BID dose resulted in an approximately half-maximal increase 
after 12 weeks of study. Shorter durations of treatment (4 weeks) with 10 µg BID of relamorelin, 
as observed in Study RM-131-004, did not demonstrate this apparent increase in HbA1c in 
diabetic participants. 
Based on the efficacyand safety data, the relamorelin dose selected for this study is10 µg BID.
6 Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, isnot permitted.
6.1 Inclusion Criteria
6.1.1
Rollover Participants
Participants who were not randomization-eligible at the end of the Run-in Period of lead-in 
Studies RLM-MD-01 or RLM-MD-02are eligible to be randomizedin the study if all of the 
following criteria apply:
In the lead-in studies, participants must have met all Screening Visit and Run-in Period
criteria for randomization into theTreatment Period (including compliance with dosing,
entry of diary data into the DGSSD)except that: 
1. Theyhadzerovomiting episodes and an average daily DGSSS of ≥ 12 at the end of 
the lead-in study Run-in Period, as reportedusing the electronic hand-held device;
OR 
2. They hadvomiting episodes and anaverage dailyDGSSSof ≥ 12but < 16 atthe end 
of the lead-in study Run-in Period, as reported using the electronic hand-held device.
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6.1.2
De Novo Participants
Participants who undergo screening and run-in procedures for Study RLM-MD-04 are eligible to 
be included in the study if all of the following criteria apply:
1. Male orfemale participants aged 18 yearsor olderat Screening (Visit –2)
2. T1DM or T2DMof at least 5 years’ duration, with controlled and stable blood glucose 
levels (ie, no episodes of diabetic ketoacidosis, Hyperosmolar HyperglycemicNonketotic 
Diabetic Syndrome, or severe hypoglycemia within the 6 months preceding Screening 
[Visit –2])
3. HbA1c ≤11.0% at Screening (Visit –2) in participants being treated with oral and/or 
parenteral medications for T1DM or T2DM with the goal of achieving controlled and 
stable glucose levels
4. DG defined as at least a 3-month history prior to Screening (Visit –2) of symptoms (one of 
which must be nausea) on an ongoing basis that are suggestive of GP (eg,nausea, 
abdominal pain,postprandial fullness, bloating,vomiting,and early satiety)
5. Female participants willing to minimize the risk of inducing pregnancy for the duration of 
the clinical study and Follow-up Period
A
 female participant is eligible to participate if she is not pregnant (has a negative urine 
pregnancy result prior to randomization; see Appendix 5), not breastfeeding, and at least 
one of the following conditions applies:
a.Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR
b.A
 WOCBP who agrees to follow the contraceptive guidance in Appendix 5during the 
TreatmentPeriod and for at least7 days after the last dose of study treatment
6. Documentation of absence of an obstructing lesion on upper GI series with contrast or 
upper endoscopy
, performed at some time before the Run-in period (Visit 2) but after the 
appearanceof symptoms that led to the diagnosis of DG
7. Nausea and/orat most a single episode ofvomiting during the 2weeks prior to Screening 
(Visit –2), as ascertained by participant history
8. Delayed GE confirmed by abnormal GEBT
, defined as GE half-time (t
½) ≥ 79minutes at 
the start of the placebo-controlled Run-in Period (Visit 2of RLM-MD-01, RLM-MD-02, or 
this study). In countries where the GEBT is not available, delayed GE may be confirmed by 
abnormal scintigraphy result (> 60% retention at 2 hours or > 10% at 4 hours). Refer to the 
Study Reference Manual
9. The BMI criterion has been removed.
10.Able to provide written informed consent (IC) prior to any study procedures and willing 
and able to comply with study procedures
Additional inclusion criteria for randomization after the 2-week, placebo Run-in Period:
11.Compliance with the entry of data intothe hand-held electronic device on at least 10 of 
14days during theRun-in Period 
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12.Compliance with administration of SC twice dailyinjections, as evidenced by entries made 
by the participantusing the electronic, hand-held device on at least 10 of 14days during the 
Run-in Period 
13.The average of thedailyDGSSS from the 2-week, Run-in Period must be ≥ 12
6.2 Exclusion Criteria
6.2.1
Both Rollover and De Novo Participants
1. Corrected QT Interval (QTc) > 470 msec in the absence of right or left bundle branch 
block, other intraventricular conduction delay (IVCD) with QRS duration >120 msec, or 
paced beat on the ECG obtained at Screening (Visit 1).
2. Participants with a known allergy or hypersensitivity to the study treatments and their 
excipients (ie, mannitol or phenol)
6.2.2
Rollover Participants
Participants will be excluded from this study if any of the lead-in study exclusion criteriaapply
at Screening (Visit 1) and at the end of the Run-in Period (Visit 3) for randomization into the 
Treatment Period of Studies RLM-MD-01 and RLM-MD-02, except as specified in the inclusion 
criteria (Section 6.1).
6.2.3
De Novo Participants
1. Symptomatic Irritable Bowel Syndromeat Screening (Visit –2)
2. Small intestinal bacterial overgrowth (SIBO) at Screening (Visit –2)
3. History of anorexia nervosa, binge-eating, bulimia, or other eating disorder within 5years 
of Screening (Visit–2)
4. History of intestinal malabsorption (including celiac disease even if well-controlled on a 
gluten-free diet) or pancreatic exocrine insufficiency; also, history of non-celiac gluten 
sensitivity
5. History of belching disorders, other nausea and vomiting disorders (eg, chronic nausea 
and vomiting syndrome, cyclic vomiting syndrome, cannabinoid hyperemesis syndrome), 
or rumination syndrome
6. History of chronic obstructive pulmonary disease or other causes of pulmonary 
dysfunction that have resulted in CO2 retention
7. Gastric or duodenal ulcer within 3 months of Screening (Visit 1)
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8. Evidence of hepatic disease defined as alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) ≥ 3 xULN, and/or direct bilirubin ≥2 x ULNat Screening 
(Visit-2)
9. History of malignancy in the 3years prior to Visit 1, except for adequately treated basal 
cell or squamous cell skin cancer, or in situ cervical cancer
10.Currently receiving parenteral feeding or presence of a nasogastric or other enteral tube 
for feeding or decompression
11.Use of metoclopramide, domperidone, prucalopride, macrolide antibiotics 
(eg,erythromycin, clarithromycin,azithromycin), or other drugs considered to be GI pro-
motility agents(Table 7–2) for at least 10 daysprior to the start of the Run-in Period 
(Visit–1)
12.Positive results on the urine drug screen at Screening (Visit -2). The sponsor may permit a 
participant with a positive urine drug screen (UDS) by immunoassay at Screening to 
continue in screening while confirmatory testing by a more specific method is carried out 
on an aliquot of the original urine sample. If the confirmatory test is negative, the initial 
positive UDS will be considered to have been a false-positive urine drug screen and the 
participant can continue in screening. Confirmatory testing will be done at the discretion 
of the sponsor and must be approved by the sponsor prior to analysis.Thesignificance of 
a positive screen result for drugs prescribed for the participant (eg, barbiturates, 
benzodiazepines, amphetamines, but not opioids or cannabinoids) shouldbe assessed by 
the Investigatoras to whether their stable-dose usage is clinically appropriate, and, 
therefore, should not be exclusionary; use of these drugs on an as-needed basis is not 
allowed.  See Section 6.4for additional details regarding positive urine drug screen.
13.Currently taking opiates, or expecting to use opiates during the course of the clinical study. 
(see Section 7.7.1for an exception to this prohibition)
14.Treatment with glucagon-like peptide-1(GLP-1) agonist for at least 6weeks prior to the 
start of the Run-in Period (Visit –1) 
15.History of pyloric injection of botulinum toxin within 6 months of screening
16.History of gastric surgery such as fundoplication, gastrectomy, gastric pacemaker 
placement, vagotomy, or bariatric procedure (a history of diagnostic endoscopy is not 
exclusionary) 
17.Randomizationin any previous study in which relamorelin was a treatment
18.Estimated glomerular filtration rate (eGFR) of < 30 mL/min 
19.Current enrollment in an investigational drug or device study or participation in such a 
study within30 days of entry into this study
20.Allergic to, or intolerant of egg, wheat, milk, or algae, as these are components of the 
GEBT study meal 
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21.Females who are pregnant, nursing, or planning a pregnancy during the study. For females 
who are of childbearing potential, see Appendix5
22.The participant has a condition or is in a situation which, in the investigator’s opinion, 
may put the participant at significant risk, may confound the study results, or may 
interfere significantly with the participant’s participation in the study
23.Participant is directly or indirectly involved in the conduct and administration of this study 
as an investigator, subinvestigator, study coordinator, other study staff member, or 
employee of Allergan, Inc.; or the participant is a first-degree family member, significant 
other, or relative residing with one of the above persons involved directly or indirectly in 
the study; or the participant is enrolled in this study at another clinical study site
24.Functional dyspepsia diagnosed before the diagnosis of diabetes mellitus
25.Hypersensitivity to the study treatments and their excipients (ie, mannitol or phenol)
26.Corrected QC Interval (QTc) > 470 msec in the absence of right or left bundle branch 
block, other intraventricular conduction delay (IVCD) with QRS duration > 120 msec, or 
paced beat on theECG obtained at Screening (Visit 1)
6.3 Lifestyle Restrictions
There are no specific dietary restrictions in the study
. It is expected that participantsare aware of 
the importance of maintaining reasonable consistency in timing and size of meals (and 
specifically carbohydrate intake) for achieving adequate control of hyperglycemia but appreciate 
that the presence ofGPmay make this difficult.
For timing of meals around the GEBT, refer to the Study Reference Manual.
6.4 Screen Failures
For de novo participants, screen failures are defined as participants who consent to participate in 
the clinical study but are not subsequently randomly assigned to study treatment. Screen failures 
can fail to meet criteria for random assignment to study treatment in the study either before or 
after participation in the Run-in Period.
De novo participants who do not meet the criteria for participation in this study (screen failure) 
before entering the Run-in Period may be rescreened once if the reason for screen failure is only 
because of Inclusion Criterion 3 “HbA1c ≤11.0% at Screening (Visit -2).” In this specific 
situation, the participant may be rescreened after at least one month and no more than 6 months 
of further effort to achieve improved glycemic control, as indicated by HbA1c being ≤11.0%. 
The sponsor may permit a participant with a positive urine drug screen by immunoassay
, at 
Screening (Visit -2) to continue in the Screening Period while confirmatory urine drug screen 
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testing by a more specific method is carried out on an aliquot of the original urine sample.  If the 
confirmatory test is negative, the initial positive urine drug screen will be considered to have 
been a false-positive urine drug screen and the participant can continue in screening.  
Confirmatory testing will be done at the discretion of the sponsor and must be approved by the 
sponsor prior to analysis.  The significance of a positive urine drug screen result for drugs 
prescribed for the participant (ie, barbiturates, benzodiazepines, amphetamines, but not opioid or 
cannabinoids) should be assessed by the Investigator as to whether their stable-dose usage is 
clinically appropriate, and if so, should not be exclusionary; use of the prescribed drugs on an as-
needed basis is not allowed.
Rescreening of a participant for any other reason is up to the discretion of the Sponsor and must 
be approved by the Sponsor prior to any rescreening procedures. The timeframe for rescreening 
is up to 6 months from the time of screen failure. Participants who enter the Run-in Period will 
not be allowed to be rescreened. Rescreening requires that a participant be assigned a new 
participant number and after repeating the Informed Consent Process, undergo all original 
screening assessments.
A
 minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography
, screen failure details, eligibility criteria, and any SAE.
7 Treatments
Study treatment is defined as any investigational treatments, marketed product, or medical device 
intended to be administered to a study participant according to the study protocol.
7.1 TreatmentsAdministered
Participants who meet study entry criteria will be randomized in a 2:1ratio to blinded treatment 
with relamorelin 10 µg or placebo. At Visit 1,participants will self-administer study treatment in 
the presence of study center personnel.
After Visit 1, participants are to self-administer study treatment twice daily SC, with the first 
daily dose being administered within approximately30 minutes before the morning meal 
(ie,breakfast, at approximately 08:00) and the second daily dose within approximately 
30minutes beforethe evening meal (ie,dinner, at approximately 18:00). If a participant does not 
eat morning or evening meals, study treatment should be administered duringtypical meal times 
(eg, 06:00 to 09:00 and 17:00 to 20:00). 
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Should a participant miss a dose prior to either the morning or evening meal, he/she should 
adjust his/her study treatment administration as follows:
If within 6 hours of the normal dosing time relative to the morning or evening dose, the 
participant should self-administer the dose at that time
If later than 6 hours after the normal dosing time relative to the morning or evening dose, the 
participant should not self-administer the dose. Resume normal dosing at the next scheduled 
time (ie, that evening if the morning dose was missed, or the next morning if the evening 
dose was missed)
Participants should rotate injection sites in the abdomen.
Study treatment will be dispensed as pen injectors withpre-filled cartridges of either relamorelin
or placebo. Study treatment details are provided in Table 7–1.
Table 7–1 
Study Treatment Details
Study Treatment
Relamorelin
Placebo
Dosage Formulation
Pre-Filled Cartridge in Multi-dose 
Pen Injector
Pre-Filled Cartridge in Multi-dose 
Pen Injector
Unit Dose Strength
10 µg dose
N/A
Route of Administration
Subcutaneous
Subcutaneous
Dosing Instructions
Administer twice daily
Administer twice daily
Packaging and Labeling
Study treatment will be provided in 
a single unit carton. Each carton 
will be labeled as required per 
country requirement.
Study treatment will be provided in a 
single unit carton. Each carton will 
be labeled as required per country 
requirement.
Manufacturer
Baxter (Prefilled Cartridge)
Allergan (Assembled Pen)
Baxter (Prefilled Cartridge)
Allergan (Assembled Pen)
Injection Device
Utilize Multi-dose Pen Injector for 
the administration of the study 
treatment or placebo.
Refer to the Relamorelin Pen 
Investigational Directions for Use 
for detailed instructions on use of 
the injection device.
Each pen injector is to be used for 
28 days.
Utilize Multi-dose Pen Injector for 
the administration of the study 
treatment or placebo.
Refer to the Relamorelin Pen 
Investigational Directions for Use 
for detailed instructions on use of the 
injection device.
Each pen injector is to be used for 
28days.
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7.1.1
Study Supplies
1. The Allergan-manufactured medical devices (or devices manufactured for Allergan by a third 
party) provided for use in this study are: (1) Prefilled Cartridge, and (2) Multi-dose Pen 
Injector.
2.Instructions for medical device use are provided in Relamorelin Pen Investigational 
Directions for Use.
3. Medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study (see 
Appendix7).
7.2 Dose Modification
Not applicable
7.3 Method of Treatment Assignment
All participants will be centrally assigned to randomized study treatment using an interactive 
web response system (IWRS). Before the study is initiated, the log-in information and directions 
for the IWRS will be provided to each site.
At the beginning of the 52-week Treatment Period, participants will be randomized in a 2:1 ratio 
to blinded treatment withrelamorelin10 µg or placebo.
Study treatmentwill be dispensed at the study visits indicated in the SoA
 (Section2). 
Returned study treatmentshould not be re-dispensed to the participants.
7.4 Blinding/Masking
The investigator, investigational staff, and participant will be fully blinded to study treatment 
during the 52-week Treatment Period. All study treatment will be provided in identical pen 
injectors and cartons to maintain blinding of the study.
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’
s treatment 
assignment is warranted. Participant safety must always be the first consideration in making such 
a determination. If the investigator decides that unblinding is warranted, the investigator is 
encouraged to contact the sponsor prior to unblinding a participant’s treatment assignment unless 
this could delay emergency treatment of the participant. If a participant’s treatment assignment is 
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unblinded, the sponsor must be notified within 24 hours after breaking the blind. The date and 
reason that the blind was broken must be recorded in the source documentation and case report 
form, as applicable.
7.5 Preparation/Handling/Storage/Accountability
1. Theinvestigator or designeemust confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved beforeuse of the study treatment.
2. Only participants enrolled in the study may receive study treatment,and only authorized site 
staff may supply or administer study treatment.All study treatments must be stored in a 
secure,environmentally controlled,and monitored (manual or automated) area in accordance 
with the labelledstorage conditions with access limited to the investigator and authorized site 
staff.
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability
, reconciliation, and record maintenance (ie,
receipt, reconciliation,and final disposition records).
4. Further guidance and information for the final disposition of unused study treatment are 
provided in the Study Reference Manual. 
7.6 Treatment Compliance
Study treatment compliance will be closely monitored by assessing the participant’s daily 
reporting of self-administered study treatment on the electronic hand-held device. Before 
dispensing new study treatment, study site personnel will make every effort to collect all used 
and unused study treatment.
In the event of early termination, compliance will be assessed using the available daily reports on 
the hand-held device and/or by the coordinator depending on when the termination occurs.In the 
event of AE or intercurrent illness, dosing of study treatment can be stopped temporarily, for a 
maximum duration of 3 days. Should longer cessation of dosing be necessary, the investigator 
should contact the sponsor(Section8.1.1).
The study centers will keep an accurate drug disposition record that specifies study treatment 
dispensed to each participant and the date of dispensing.
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7.7 Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the studymust be recorded on the electronic case report form (eCRF) alongwith:
Reason for use
Dates of administration including start and end dates
Dosage information including dose and frequency
As much as possible, the dose and frequency ofall concomitant medications taken for chronic 
conditionswith the exception ofdiabetes mellitus(see Section 7.7.2—Permitted Treatments)
should be held stable during the study. The sponsorshould be contacted if there are any questions 
regarding concomitant or prior therapy
.
7.7.1
Prohibited Treatments and Washout Before the Study
The classes of drugs prohibited in the study are, with the exception SLGT-1 and SGLT-2 
inhibitors,thosethat affect GI motility, either positively or negatively
, and therefore could 
confound the assessment of the efficacyof study treatment on the signs and symptoms of DG.
The SGLT-1 and SGLT-2 inhibitors are prohibited Their mechanism of action is through causing 
increased glycosuria, which may affect interpretation of the GEBT results.
Table 7–2provides a list of drug classes and treatments that are prohibited during thisstudy and 
require washout during the Run-in Periodsof the current study and the lead-in Studies (RLM-
MD-01or RLM-MD-02).
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Table 7–2
Prohibited Medications and Washout Requirements
Drug Class/Treatment
Washout Required Prior to Baseline
Sodium-glucose co-transporter-2 (SGLT-1 or SGLT-2) 
inhibitors: Empagliflozin, canagliflozin, dapagliflozin, etc.
Prohibited only 3 days prior to the GEBT 
done in a subset of participants at a subset of 
sites at Visit 4 or the Early Termination Visit
Pro-motility agents:Metoclopramide, macrolide 
antibiotics (eg,erythromycin, clarithromycin, 
azithromycin), domperidone, prucalopride, or other drugs 
considered to be GI pro-motility agents
Rollover Participants:  10 daysprior to the 
start of the Run-in Periodof the Lead-instudy
De novo Participants:  10days prior to the 
start of the Run-in Period of this study,
RLMMD-04
Anticholinergics: Drugs withananti-cholinergic 
mechanism ofaction as the basis oftheirtherapeutic 
benefit, not those that have anti-cholinergic activity as a 
side effect
Anti-emetics (Used for more than 1 day a week, or 
participant requires an anti-emetic drug once weekly 
repeatedly (ie, for 3consecutive weeks or more), the 
investigator should contact the sponsor to discuss the safety 
of the participant continuing study treatment.)
Amylin analogue: pramlintide
5HT4 agonists (cisapride, tegaserod, and prucalopride)
Opioidsa(eg, tramadol)
Washout period is not applicable as the use of 
opioids is not allowed.  See Exclusion Criteria 
#12 and #13.
Glucagon-like peptide-1 (GLP-1) agonists: Exenatide, 
liraglutide, etc.
Rollover Participants:  6weeks prior to the 
start of the Run-in Periodof the Lead-instudy
De novo Participants:  6 weeks prior to the 
start of the Run-in Period of this study,
RLMMD-04
Botulinumtoxin injections (eg, Botox®) by pyloric 
injection only; injection of Botox in other parts of the body 
is allowed
6 months prior to screening (Visit –2)
a 
Exception to prohibition: An opioid prescribed for severe pain following a surgical operation, dental procedure, 
or injury may be taken as directed for up to 72 hours a maximum of two times during the study.
7.7.2
Permitted Treatments
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins,
and/or herbal supplements) that the participantis receiving at the time of enrollmentor receives 
during the study must be recorded in the eCRF along with:
Indication
Dates of administration including start and end dates
Dosage information including dose and frequency
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DG participants enrolled in this study will likely consist mostly of patients receiving one or more 
prescription medications for blood-glucose control. Good clinical practice allows for frequent 
adjustment of medication by patients and their health care providers to minimize large 
fluctuations in glycemia, and this practice is encouraged in this study. It should be remembered 
that certain diabetic drugs (see Table 7–2) delay GE and are prohibited during this study
. Other 
therapy considered necessary for the participant’
s welfare may be given at the discretion of the 
investigator. If the permissibility ofa specific medication/treatment is in question, please contact 
the sponsor
.
The sponsor or designee shouldbe contacted if there are any questions regarding concomitant or 
prior therapy
.
7.7.3
Rescue Medicine
Use of medications that may impact efficacy evaluations is strongly discouraged at any time after
Visit 1 in the study. However, participants who experience severe symptoms of GP may receivea 
single day of treatment per week with an anti-emetic drug, but should avoid such treatment, if
possible, during the 2-week Run-in Period, and on the day prior to and day of clinic visitsduring 
the Treatment Period. If aparticipant requires an anti-emetic drug (eg, 5-HT3 receptor 
antagonists, NK1 receptorantagonists) for more than one day aweek, or requires an anti-emetic 
drug once weekly repeatedly(ie, for 3 consecutive weeks or more), the investigator should 
contact the sponsor to discuss the safety of the participant continuing study treatment.
The date of rescue-medication administration as well as the name and dosage regimen of the 
rescue medication should be recorded in the concomitant medications page of the eCRF.
7.8 Treatment after the End of the Study
Participants who complete the study should follow up with the investigator regarding treatment 
at the end of the study. 
8 Discontinuation/WithdrawalCriteria 
Reasons for discontinuation from study treatment and/or the study may include the following:
Adverse event
Completed
Death
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Failure to meet entry criteria
Lack of efficacy
Lost to follow-up
Other
Investigatordecision
Pregnancy
Protocol deviation
Site terminated by sponsor
Study terminated by sponsor
Withdrawal by participant
The reason for discontinuation should be clearly documented on the appropriate eCRF.
Discontinuation of study treatmentalso requiresdiscontinuation from the study.(See Appendix8
for Standard Discontinuation Criteria/Definitions.)
8.1 Discontinuation ofStudy Treatment
Discontinuation of study treatment also requires discontinuationfrom the study. The following 
criteria should be evaluated:
Special attention should be paid to the appearance of abnormal laboratory test results 
suggesting severe, drug-induced liver injury(DILI). Discontinuation of study treatmentfor 
abnormal liver function should be considered by the investigator when a participant meets 
criteria for Hy’s law (see Section9.2.7.1and Appendix 6) or if the investigator believes that 
it is in best interest of the participant. 
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ECGs should be carefully analyzed for findings pointing to potentially important cardiac 
events. If a clinically significant finding is identified (including, but not limited to changes 
from baseline in QT interval corrected using QT
cB or QTcFafter enrollment, the investigator 
or qualified designee should determine if the participant can continue in the study and if any 
change in participant management is needed. Generally, a QT
c value of >500 msec or an 
increase from baseline of >60 msec after start of study treatment should prompt 
discontinuation of the participantfrom the study. Review of the ECG printed at the time of 
collection must be documented. Any new clinically relevant finding should be reported as an 
AE.
Female participants who become pregnant during the study must be discontinued from 
treatment immediately and withdrawn from the study. See Section 9.2.5and Appendix 5for 
further details regarding follow-up of the participant through the pregnancy
.
See the SoA (Section 2) for data to be collected at the time of treatment discontinuation.
8.1.1
Temporary Discontinuation
In the event of AE or intercurrent illness, dosing of study treatmentcan be stopped temporarily, 
for a maximum duration of 3 days. Should longer cessation of dosing be necessary, the 
investigator should contact the sponsor.The investigator should also contact the sponsor should 
either recurrence of the AE that prompted discontinuation or the appearance of a new AE that 
requires discontinuation be experienced after reintroduction of treatment to discuss the safety of 
this participant continuing study.
8.2 Withdrawalfromthe Study
A
 participantmay withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigatorfor safety, behavioural,
compliance, or administrative reasons.An early termination visit must be performed as soon 
as possible after the decision to withdraw has been made by the participant or the decision to 
withdraw the participant has been made by the investigator
.
If the participantwithdraws consentfor disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a participantwithdraws from the study, he/she may request destruction of any samples 
taken and not tested,and the investigator must document this in the site study records.
Seethe SoAfor data to be collected at the time of study discontinuation.
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8.3 Lost to Follow Up
A
 participantwill 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.
The following actions must be taken ifa participantfails to return tothe clinic for a required 
study visit:
The site must attempt to contact the participantand reschedule the missed visit as soon as 
possible and counsel the participanton the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participantwishes to and/or should continue in the 
study.
Before aparticipantis deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant(where possible, 3 telephone calls and,if 
necessary,a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record.
Should the participantcontinue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9 Study Assessments and Procedures
Study procedures and their timing are summarized in the SoA (Section 2).
Protocol waivers or exemptions are not allowed.
Safety concernsshould be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment.
Adherence to the study design requirements, including those specified in the schedule of 
activities, is essential and required for study conduct.
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 66.5mLfor 
rollover participants or 74.5mL for de novo participants. Repeat or unscheduled samples 
may be taken for safety reasons or for technical issues with the samples.
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9.1 EfficacyAssessments
9.1.1
Key EfficacyAssessment-DGSSD
The main efficacy assessment is the DGSSD, a 7-item, patient-reported diary designed to assess 
the severity of 6 core signs and symptoms of DG—nausea, abdominal pain, postprandial 
fullness, bloating, vomiting, and early satiety—and the frequency of vomiting episodes
(Appendix 13).Participantswill report their symptoms daily from Visit 1 to Visit 4 (Day 84) in 
the DGSSD.  Thereafter, participants will report their symptoms daily for each of the 4 weeks 
preceding Visits 5, 6, and 7.  DGSSD entries are to be made daily at the same time every evening 
on the electronic hand-held device throughout the Treatment Period. Planned periods for DGSSD 
entriesare provided in the SoA (Section 2).
The severity of DG symptoms areassessed using a 0 to 10 numerical rating scale (NRS), on 
which 0 = “no” or “not at all uncomfortable” (ie, absence of the DG symptom) and 10 = “worst 
possible” or “most uncomfortable” (ie, worst experience of the DG symptom).
The overall assessment of the severity of non-vomiting symptoms is derived from the weekly 
DGSSS, as the sum of the weekly averages of the DGSSD items of nausea, abdominal pain, 
postprandial fullness, and bloating, calculated from a participant’
s daily DGSSD responses.
The range of DGSSS is 0-40 with the worst possible DGSSS for the 4 DG symptoms being40, 
and the best possible DGSSS being0. Psychometric analyses have shown that a decrease in the 
DGSSS by ≥ 8 points and a decrease in individual symptom scores by ≥2 points is recognized as 
a clinically meaningful improvement in DG symptoms by affected patients (Psychometric 
Evaluation, RTI Health, 2017).Further psychometric analyses will be conducted to confirm the 
clinically meaningful thresholdsfor improvement.
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9.2 Adverse Events
The definitions of an AE or SAEcan be found inAppendix 4.
AEswill be reported by the participantor noted by the investigator.
The investigator and anydesignees are responsible for detecting, documenting,and recording 
events that meet the definition of an AE or SAEand remain responsible for followingupAEs
that are serious, considered related to the study treatment or studyprocedures, or that caused the 
participantto discontinue thestudy treatment(see Section8). 
9.2.1
Time Period and Frequency for Collecting AE and SAE 
Information
All AEs and SAEswill be collected from the signing of theinformed consent form(ICF)until 
30days after the final visit in the study (V
isit 7) or Early Termination Visit at the time points 
specified in the SoA (Section 2).For rollover participants, ongoing AEs from lead-in Studies
RLM-MD-01 and RLM-MD-02, and new AEs that occur after the signing of the ICF for RLM-
MD-04are considered to be AEs in RLM-MD-04.
Medical occurrences that begin before the start of study treatment but after obtaining IC
(informed consent)will be recorded in the AE sectionof the eCRF and will be considered 
pretreatment AEs.
All SAEswill be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 4. The investigator will submit any updated SAE data to the sponsorwithin 
24hours of itbeing available.
Investigators are not obligated to actively seek AEor SAE in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event to be reasonably related to the 
study treatment or study participation, the investigator must promptly notify the sponsor.
The method of recording, evaluating, and assessing causality of 
AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 4.
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9.2.2
Method of Detecting AEsand SAEs
Care will be taken not to introduce bias when detecting AEsand/or SAEs. Open-ended and 
non-leading verbal questioning of the participantis the preferred method to inquire about 
AEoccurrences.
9.2.3
Follow-up of AEsand SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant
at subsequent visits/contacts.All AEs/SAEsand non-serious AEs of special interest ([AESI] as 
defined in Appendix 4) will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participantis lost to follow-up (as defined in Section8.3). Further 
information on AE/SAE follow-up procedures is given in Appendix 4.
9.2.4
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsorof an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study treatment under clinical investigation are met. 
The sponsorhas a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.The 
sponsorwill comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority
, institutional review boards (IRBs)/independent ethics 
committees (IECs),and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions(SUSARs)according to local regulatory requirements and sponsorpolicy and 
forwarded to investigators as necessary
.
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg,summary or listing of SAEs) from the sponsorwill review and then 
file it along with the investigator’s brochureand will notify the IRB/IEC, if appropriate 
according to local requirements.
9.2.5
Pregnancy
Details of all pregnancies in female participants and female partners of male participants will 
be collected after the start of study treatment and until 7 days after the last dose.
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If a pregnancy is reported, the investigator should inform the sponsorwithin 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.
Abnormal pregnancy outcomes (eg,spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
9.2.6
Medical Device Incidents (Including Malfunctions)
Medical devices are being provided for use in this study for the purposes of study treatment self-
administration. In order to fulfill regulatory reporting obligations worldwide, the investigator is 
responsible for the detection and documentation of events meeting the definitions of incident or 
malfunction that occur during the study with such devices. 
The definition of a medical device incident can be found in Appendix7.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes outlined in 
Section9.2and Appendix 4of the protocol. 
9.2.6.1
Time Period for Detecting Medical Device Incidents
Medical device incidents or malfunctions of the device that result in an incident will be 
detected, documented, and reported during all periods of the study in which the medical 
device is used.
If the investigator learns of any incident at any time after a participant has been discharged 
from the study
, and such incidentis considered reasonably related to a medical device 
provided for the study
, the investigator will promptly notify the sponsor.
The method of documenting medical device incidents is provided in Appendix 7.
9.2.6.2
Follow-up of Medical Device Incidents
All medical device incidents involving an AE will be followed and reported in the same
manner as other AEs(see Section 9.2). This applies to all participants, including those who 
discontinue study treatment or the study
.
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident.
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New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator.
9.2.6.3
Prompt Reporting of Medical Device Incidents to Sponsor
Medical device incidents will be reported to the sponsor within 24 hours after the investigator 
determines that the event meets the protocol definition of a medical device incident.
9.2.6.4
Regulatory Reporting Requirements for Medical Device 
Incidents
The investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for thesponsor to fulfillthe legal responsibility
, if 
needed, to notify appropriate regulatory authoritiesand other entities about certain safety 
information relating to medical devices being used in clinical studies.
The investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of incidents to the IRB/IEC.
9.2.7
Adverse Events of Special Interest
9.2.7.1
Hy’s Law
Study site personnel must report every participant who meets Hy’s Law criteria,which are as
follows: 
Alanine aminotransferase (ALT)or aspartateaminotransferase (AST)≥ 3× upper limits of 
normal (ULN) AND 
Total bilirubin ≥ 2× ULN AND 
Alkaline phosphatase <2× ULN
Typically, all analytes will be obtained from the same sample, but they may come from multiple 
samples taken within a 24-hour period. This requirement applies from the time the participant 
signs the ICF for the study until 30 days after the final protocol-defined study visit or the last 
known dose of study treatment(if the final visit does not occur). 
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A
 laboratory alert for Hy’slaws cases will be in place. Investigators and the sponsor must be 
immediately notified when the above criteria have been met. 
 
 
 
 
Every effort to determine the cause of the liver 
enzyme abnormalities must be made, and close monitoring should be initiated in conjunction 
with the MSP and in accordance with the FDA Guidance for Industry
, Drug-Induced Liver 
Injury: Premarketing Clinical Evaluation, July 2009.
Additional details regarding liver safety assessments and follow up are provided in Appendix 6.
9.2.7.2
Inadequate Control of Diabetes:  Hyperglycemia and 
Hypoglycemia
The irregular and delayed emptying of the stomach in DG has a major effect on the presentation 
of ingested carbohydrate to the small intestine for absorption, complicating the dosing of 
hypoglycemic agents (including insulin) used to manage glycemia. Participants should be closely 
monitored for changes to their diabetes control while in the study, and eventsrelated to 
hyperglycemia or hypoglycemia that are considered to be clinically significant should be 
reported as AEs(Section 9.2.1). 
9.2.7.3
Major Adverse Cardiovascular Events 
Patients with DGtypically have long-standing diabetes mellitus, which predisposes them to 
develop macrovascular (and microvascular) complications. These include Major Adverse 
Cardiovascular Events (MACE) commonly defined as death from cardiovascular causes, non-
fatal myocardial infarction, non-fatal stroke, and often also includingrevascularization (coronary 
or peripheral)procedures, and hospitalization for unstable angina pectoris. 
In this study, occurrence of any of these events should be reported to the MSP within 24 hours of 
being made aware on the SAE form, followed by a complete report including narrative 
description of the event, test results, and copies of hospital records, if applicable.All reports of 
possible MACE will be adjudicated internally in a blinded fashion by a committee of qualified 
physicians on a periodic basis depending on the frequency of reported events. The functioning of 
the committee will be governed by charter.
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9.2.8
Medication Errors
Medication error refers to any unintended error in the dosing and/or administration of the study 
treatmentas per instructions in the protocol. Medication errors generally fall into 4 categories as 
follows:
Wrong study drug/device
Wrong dose (including dosing regimen, strength, form, concentration, amount)
Wrong route of administration
Wrong participant (ie,not administered to the intended participant)
Medication errors include occurrences of overdose and underdose of the study treatment.
Overdose: Unintentional administration of a quantity of the study treatmentgiven per 
administration or per day thatis above the maximum recommended dose (10 µgBID or 
20µg/day) according to the reference safety information or protocol for the study treatmentor 
comparator as applicable. This also takes into account cumulative effects due to overdose. 
Underdose: Unintentional administration of a quantity of the study treatmentgiven per 
administration or per day thatis under the minimum recommended dose according to the 
reference safety information or protocol.Since there is no clinical information on the efficacy of 
relamorelinat a dose less than 10 µgBID, a dose of 10 µgonce dailyshould be considered an 
underdose.
9.3 Treatment of Overdose
The sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose,the investigator should:
1. Contact the MSPimmediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
treatment can no longer be detected systemically.
3. Document the quantity of the excess dose as well asthe duration of the overdosein thesite’s 
source documents for the participant.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation withthe MSPbased on the clinical evaluation of the participant.
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9.4 SafetyAssessments
Planned timepoints for all safety assessments are providedin the SoA (Section 2).
9.4.1
Physical Examinations
Complete physical examinations (excluding pelvic exam in women and genital exam in men, and 
rectal exam in both genders) are to be performed. Symptom-directed (abbreviated) physical 
examinations, including evaluation of the injection sitesfor clinically significant reactions, may 
be conducted as required at other study visits.
Participants should be weighed with no shoes, in light clothing, without any outerwear
. Height 
shouldbe measured only at the first study visit (at V
isit 1 of lead-in Studies RLM-MD-01 or 
RLM-MD-02 for rollover participants; at Visit –2 of RLM-MD-04 for de novo participants).
Any abnormality noted on the physical examination done at Visit 7or the early termination visit 
that was not present on thephysical examination at screeningshould be reported as an AE if 
considered by the investigator to be clinically significant.
9.4.2
Vital Signs
Heartrate(HR), respiratory rate, systolic and diastolic blood pressure(BP), andtemperature 
will be assessed; the method for measuring temperature will be per the site’s preference
BP and HRmeasurements will be assessed in the sitting position with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available.
BP and HRmeasurements should be preceded by at least 3minutes of rest for the participant 
in a quiet setting without distractions (eg,television, cell phones).
Vital signsare to be taken before blood collection for laboratory tests.  
9.4.3
Electrocardiograms
Single12-lead ECG will be obtained as outlined in the SoA (see Section 2) using an ECG 
machine that automatically calculates the HRand measures PR, QRS, QT, and QT
c intervals. 
Refer to Section 8.1for QTc withdrawal criteria.
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9.4.4
Clinical Safety Laboratory Assessments
SeeAppendix 2for the list of clinical laboratory tests to be performed and refer to the SoA 
for the timing and frequency.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the 
AEsection of the eCRF. The 
laboratory reports must be filed with the source documents.Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30daysafter the last dose of study treatment should be 
repeated until the values return to normal or baseline, or are no longer considered clinically 
significant by the investigator or MSP.
o If such values do not return to normal/baselinewithin a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor
notified.
o All protocol-required laboratory assessments, as defined in 
Appendix2, must be 
conducted in accordance with the laboratory manual and the schedule of activities.
o If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratoryrequire a change in participantmanagement or are 
considered clinically significant by the investigator (eg,SAE or AE or dose 
modification), thenthe results must be recorded in theeCRF.
9.4.5
Self-monitoring of Blood Glucose
Participants will be strongly encouraged to carry out self-monitoring of blood glucose (SMBG) 
at home in order to achieve and maintain optimum glucose control during the study. This is 
almost always required by patients with T1DM and is good clinical practice in patients with 
T2DM. At the start of the Run-in Period, the Sponsor willprovide each roll-over and de novo 
participant with a glucose monitor, test strips, and all supplies necessary for testing finger-stick 
capillary blood glucosethroughout the study. It is recommended that this be done twice daily
, 
pre-breakfast (fasting) and approximately 2 hours post-lunch or dinner (whichever is the larger 
meal). 
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Information from SMBG, in addition to that provided by values of HbA1c and fasting blood 
glucose, will be available to investigators for decision-making regarding adjustment of diabetic 
medications, diet, and exercise (or, alternatively
, for decision-making regarding referral of the 
participantto his/her health care provider for the same purpose). 
9.5 Pharmacokinetics
Pharmacokineticparameters are not evaluated in this study.
9.6 Pharmacodynamics
Pharmacodynamicparameters are not evaluated in this study.
9.7 Genetics
Genetics are not evaluated in this study.
9.8 Biomarkers
Biomarkers are used in the study only to help characterize the diabetes mellitus of individual 
participants as either type 1or type 2.
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10Statistical Considerations
10.1Sample Size Determination
There wereno extensive sample size calculations performed formally for this study. Asample 
size of approximately 600 participants (with randomization ratio treatment to placebo of 2:1) will 
provide 90% power to detect a statistically significant difference in response rate from placebo in
both the 4-symptom composite DGSSS endpoint (assuming a placebo rate of 14% and a
treatment rate of 35%) and in the vomiting response endpoint (assuming a placebo rate of 11%
and a treatment rate of 26%). Assumed response rates were those calculated from Study
RM-131-009.
10.2Populations for Analyses
The analysis populations will consist of participants as defined in Table 10–1.
Table 10–1
Analysis Populations
Population
Definition
Screened
All participants who sign informed consent
Intent-to-treat (ITT)
All randomized participants
Modified intent-to-treat (mITT)
All randomized participants with ≥ 1 postbaseline assessment of 
DGSSD 
Safety
All participants who received ≥ 1 administration of study 
treatment
10.3Statistical Analyses
The statistical analysis plan (SAP) will be developed and finalized beforedatabase lock and will 
describe the participantpopulations to be included in the analyses, and procedures for accounting 
for missing data. This sectionis a summary of the planned statistical analyses of the key
endpoints.
10.3.1
Key Statistical Methodology
The methodologies defined in Table 10–2apply as specified to individual endpoints defined in 
theSAP. 
All statistical tests will be 2-sided hypothesis tests performed at the 5% level of 
significance for main effects. All CIswill be 2-sided 95% CIs, unless stated otherwise.
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Table 10–2
Statistical Methodology
Methodology
Description
Categorical counts

Number of participants in individual categories
o
Participants with ≥ 1 qualifying event counted once per individual category
Categorical 
descriptives

Number and percentage of participants in individual categories
o
Participants with ≥ 1 qualifying event counted once per individual category

N1 if percentage denominator ≠ number of participants in the population (standard 
percentage denominator)
o
N1 = participants with nonmissing baseline value
Continuous 
descriptives

N1, mean, SD, median, minimum, maximum

N1 = participants with nonmissing value
CFB descriptives

Continuous descriptives for baseline, postbaseline, and change from baseline (CFB) 
values

N1 = participants with nonmissing values at both baseline and the specified 
postbaseline analysis visit
CFB MMRM

Continuous descriptives and standard error (SE) for baseline, postbaseline, and CFB 
values
o
Estimates derived from mixed model for repeated measures (MMRM)for CFB 
value controlling for factors (treatment group, site) and covariates (baseline 
value)

Least squares (LS) means and standard errors

LS mean differences, standard errors, and CIs vs placebo

P-values from contrast t-test comparing treatment group vs 
placebo

N1 = participants with nonmissing values at both baseline and the specified
postbaseline analysis visit
10.3.2
Efficacy Analyses
10.3.2.1
Key Endpoints
Table 10–3displays the keyefficacy endpoints that will be analyzed for the mITT population. All 
other efficacy endpoints and analyses will be defined in the SAP.
Table 10–3
Key Endpoints
Key Endpoints
Description
Timing
Methodology
Key Endpoints
CFB toWeek 12 in 
weekly DGSSS
Change from baseline to Week 12 in 
weekly DGSSS
Week 12
CFBMMRM
CFB to Week 52 in 
weekly average DGSSS
Change from baseline in average of the 
weekly average DGSSSfrom Weeks 49 to 
52
Week 49-Week 52
CFB MMRM
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10.3.2.2
Missing Data
Handling of missing data will be provided in the SAP.
10.3.3
Safety Analyses
All safety analyses will beperformed on the Safety Population.
The following safety categories will be summarized as appropriate (eg, categorical or continuous 
descriptives, shift tables) for the safety population and will be fully defined in the SAP.
AEs
o Clinically significant hyperglycemia-and hypoglycemia-related events
Clinical laboratory assessments
o Hy’s law cases
Vital signs
ECGs
Study-specific assessments
o HbA1c
10.3.5
Interim Analyses
In addition to the above, monitoring of participant safety data will be performed by an 
independent Data and Safety Monitoring Board (DSMB).  The DSMB will review interim safety 
data at defined intervals throughout the study
.  The DSMB will communicate their 
recommendations to the Sponsor after each meeting, but will serve in an advisory capacity only; 
the Board will not be empowered to stop the study or require changes to the protocol.  Study 
conduct may be interrupted or terminated by the Sponsor based on DSMB recommendations if 
safety data become available that appear to represent an undue risk to the study participants’
 
health or well being.  Further details of the DSMB (composition, policy, and procedures) are 
specified in a separate DSMB charter.
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11References
All references are available upon request.
Acosta A, Camilleri M, Kolar G, et al. Relamorelin relieves constipation and accelerates colonic 
transit in a phase 2, placebo controlled, randomized trial. Clin Gastroenterol Hepatol.
2015;13(13):2312-9.e1.
Acosta A,Camilleri M, Busciglio I, et al. Short-term effects of relamorelin on descending colon 
motility in chronic constipation: a randomized, controlled trial. Dig. Dis. Sci. 2016;61(3):852-
860.
Bharucha AE. Epidemiology and natural history of gastroparesis. Gastroenterol Clin North Am. 
2015;44(1):9-19.
Camilleri M, Bharucha AE, Farrugia G. Epidemiology, mechanisms, and management of diabetic 
gastroparesis. Clin Gastroenterol Hepatol. 2011;9(1):5-12.
Camilleri M, Parkman HP, Shafi MA, et al. Clinical guideline: management of gastroparesis. Am 
J Gastroenterol. 2013;108(1):18-37.
Centers for Disease Control and Prevention. Measuring Healthy Days. 
Atlanta, Georgia: CDC, 
November 2000.
de la LogeC, Trudeau E, Marquis P, et al. Cross-cultural development and validation of a patient 
self-administered questionnaire to assess quality of life in upper gastrointestinal disorders: the 
PAGI-QOL. Qual Life Res. 2004;13(10):1751-1762.
de la Loge C, Trudeau E, Marquis P, et al. Responsiveness and interpretation of a quality of life 
questionnaire specific to upper gastrointestinal disorders. Clin Gastroenterol Hepatol. 
2004;2(9):778-86.
Dornonville de la Cour C, Lindström E, Norlén P
, et al. Ghrelin stimulates gastric emptying but 
is without effect on acid secretion and gastric endocrine cells. Regul Pept.2004;120(1-3):23-32.
Jung HK, Choung RS, Locke GR, et al. The incidence, prevalence and survival of gastroparesis 
in Olmsted County
, Minnesota: 1996-2006. Gastroenterology.2008;134(suppl 1):A534–A535.
Koch KL, Hasler WL, Yates KP, et al. Baseline features and differences in 48 week clinical 
outcomes in patients with gastroparesis and type 1 vs type 2 diabetes. Neurogastroenterol Motil. 
2016;28(7):1001-1015.
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Murray CDR, Martin NM, Patterson M, et al. Ghrelin enhances gastric emptying in diabetic 
gastroparesis: a double blind, placebo controlled, crossover study. Gut.2005;54(12):1693–1698. 
Parkman HP
, Hasler WL, Fisher RS. American Gastroenterological Association technical review 
on the diagnosis and treatment of gastroparesis. Gastroent.2004;127:1592-1622.
Parkman HP, Yates K, Hasler WL, et al. National Institute of Diabetes Digestive Kidney 
Diseases Gastroparesis Clinical ResearchConsortium. Similarities and differences between 
diabetic and idiopathic gastroparesis. Clin Gastroenterol Hepatol. 2011; 9:1056–1064.
Rayner CK, Samsom M, Jones KL, et al. Relationships of upper gastrointestinal motor and 
sensory function with glycaemic control. Diabetes Care.2001;24:371–381.
RTI Health Solutions, Psychometric Evaluationofthe Diabetic GastroparesisSymptom Severity 
Diary UsingRM-131-009 Data, Report on file. 
Allergan, Jersey City NJ, 2017.
Trudel L, Bouin M, Tomasetto C, et al. Two new peptides to improve post-operative gastric ileus 
in dog. Peptides.2003;24:531–534.
http://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/esophagus_stomach/gastro
paresis.pdf. Accessed 04Nov2015.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for 
Industry Drug-Induced Liver Injury: Premarketing ClinicalEvaluation. July2009. 
https://www.fda.gov/downloads/Guidances/UCM174090.pdfAccessed 02Jan2018.
U.S. Department of Health and Human Services, Food and Drug Administration. Draft Guidance 
for Industry Gastroparesis: Clinical Evaluation of Drugs for Treatment. July 2015. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM455645.pdf Accessed 23Nov2015.
U.S. Department Of Health And Human Services, National Institutes of Health Publication No. 
12–4348 June 2012. http://www.niddk.nih.gov/health-information/health-topics/digestive-
diseases/gastroparesis/Documents/Gastroparesis_508.pdf Accessed 03Nov2015.
WareJE, Kosinski M, Keller S. A
 12-Item Short-Form health survey: construction of scales and 
preliminary tests of reliability and validity
. Medical Care. 1996;34:220-233.
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12Appendices
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12.1Appendix 1:Abbreviations and Trademarks
ADA
anti-drug antibodies
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST 
aspartate aminotransferase
BID
twice daily
BMI
body mass index
BP
blood pressure
CDER
Center for Drug Evaluation and Research
CFB
change from baseline
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting
CSR
clinical study report
DG
diabetic gastroparesis
DGSSD
Diabetic Gastroparesis Symptom Severity Diary
DGSSS
Diabetic Gastroparesis Symptom Severity Score
DILI
drug-induced liver injury
DSMB
Data and Safety Monitoring Board
ECG
electrocardiogram
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eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
FDA
US Food and Drug Administration
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GE
gastric emptying
GEBT
gastric emptying breath test
GERD
gastroesophageal reflux disease
GHS1α
Growth Hormone Secretagogue 1 α
GI
gastrointestinal
GLP-1
glucagon-like peptide-1
GP
gastroparesis
HbA1c
glycosylated hemoglobin A1c
HEOR
health economic outcomes research
HIPAA
 
Health Insurance Portability and 
Accountability Act
HR
heart rate
HRT
hormonal replacement therapy
ICF
informed consent form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IGF-1
insulin-like growth factor-1
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IND
Investigational New Drug Application
INR
international normalized ratio
IRB
Institutional Review Board
IWRS
interactive web response system
MACE
Major Adverse Cardiovascular Events
MAR
missing at random
mITT
modified intent-to-treat
MMRM
mixed model for repeated measures
MSP
medical safety physician
NRS
numerical rating scale
QTcB
QT interval corrected for heart rate using the Bazett formula 
QTcF
QT interval corrected for heart rate using Fridericia formula 
RLM
relamorelin
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous(ly)
SF-12v2
12-item Short Form Survey (version 2)
SGLT-2
Sodium glucose co-transporter 2
SMBG
self-monitoring of blood glucose
SoA
Schedule of Activities
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SUSAR
suspected unexpected serious adverse reaction
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
ULN
upper limits of normal
US
United States of America
WOCBP
women of childbearing potential
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12.2Appendix2:Clinical Laboratory Tests 
o All clinical laboratory tests should be done after participants have fasted for at least 
8hours 
o The tests detailed inSection 9.4.4will be performed by the central laboratory
o Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections6.1and 6.2of the protocol.
o Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
o Investigators must document their review of each laboratory safety report.
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Table 12–1
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
RBC indices:
MCV
MCH
MCHC
% Reticulocytes
WBC count with differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC count
Hemoglobin
Hematocrit
Clinical 
Chemistry
BUN
Creatinine
eGFR
Potassium
Chloride
Bicarbonate
Aspartate 
aminotransferase 
(AST)
b
Total and direct 
bilirubinb
Fasting blood 
glucosea
HemoglobinA1c
Sodium
Calcium
Phosphorus
Uric acid
Alanine 
aminotransferase
(ALT)
b
Alkaline 
phosphataseb
Total protein
Albumin
Lipid profile 
(cholesterol, 
triglycerides, HDL 
cholesterol, LDL 
cholesterol (calculated)
Other Laboratory 
Assessments
C-peptide 
Anti-relamorelin 
antibodies
GADA (GAD 65)
IA-2A
ZnT8
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
Serum and urine human chorionic gonadotropin (hCG) pregnancy test ([at Visit -2 and 
Visit 1, respectively, and as noted in the SoA]as needed for women of childbearing 
potential)
Urine drug screen(to include at a minimum: amphetamines, barbiturates, benzodiazepines, 
cocaine, cannabinoids, phencyclidine, and opiatesc)at ScreeningVisit, 
BUN = blood urea nitrogen, eGFR = estimated glomerular filtration rate, GADA = glutamic acid decarboxylase 
autoantibodies, IA-2A= islet antigen–2 antibodies, MCV = mean corpuscular volume, MCH = mean corpuscular 
hemoglobin, MCHC = mean corpuscular hemoglobin concentration, RBC = red blood cell, WBC = white blood 
cell, ZnT8 = zinc transporter 8.
aSerum for all visits except for Visits 4 and 6
b  Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Appendix 6. 
cScreening for drugs of abuse will be conducted using a urine drug screen at Visit -2.
Investigators must document their review of each laboratory safety report.
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12.3Appendix 3:Study Governance Considerations
12.3.1
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and withthe following:
o Consensus ethicalprinciples derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines
o Applicable ICH Good Clinical Practice(GCP) guidelines
o Applicable laws and regulations
The protocol, protocol amendments, ICF, investigator’sbrochure,and other relevant 
documents (eg,advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
Any amendments to the protocol will require IRB/IEC approval beforeimplementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will beresponsible forthe following:
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC
o Notifying the IRB/IEC of SAEsor other significant safety findings as required by 
IRB/IEC procedures
o Providing oversight of the overall conduct of the study at the site and adherenceto 
requirements of applicable local regulations,for example 21 CFR, ICH guidelines, the 
IRB/IEC, and European regulation 536/2014 for clinical studies(ifapplicable)
12.3.2
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requestedto allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatoryauthorities.Investigators are 
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responsible for providing information on financial interests during the course of the study and for 
1yearafter completion of the study.
12.3.3
Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participantand answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement ofinformed consent that meets the requirements of 21CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act
(HIPAA)requirements, where applicable, and the IRB/IEC or study center
. 
The medical record must include a statement that written informed consent was obtained 
before the participantwas enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF.
Written documentation must be obtained in accordance with the relevant country and local 
privacy requirements, where applicable (eg, Written Authorization for Use and Release of
Health and Research Study Information [US sites] and written Data protection Consent 
[European sites]).
Participants must be re-consented to the most current version of the ICF(s)during their 
participation in the study. 
A
 copy of the ICF(s)must be provided to the participant.
Additionally, in accordance with relevant country requirements, written informed consent is to be 
obtained from each participant prior to enrollment into the study. The informed consent form 
includes explanation of the following:
1. That the study involves research
2. The objectives of the study
3. The study procedures
4. The expected duration of the participant’s participation in the study
5. The approximate number of participants involved in the study
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6. The reasonably foreseeable risks or inconveniences to the participant
7. The alternative procedures or courses of treatments that may be available to the participant, 
and their important potential benefits and risks
8. The compensation and/or treatment available to the participant in the event of study-related 
injury
9. That the participant’s participation in the study is voluntary and that the participant may 
refuse to participate or withdraw from the study at any time, without penalty or loss of 
benefits to which the participant is otherwise entitled
10.That the participant will be informed in a timely manner if information becomes available 
that may be relevant to the participant’s willingness to continue participation in the study
11.The foreseeable circumstances and/or reason under which the participant’s participation in 
the study may be terminated
12.That the monitors, auditors, the IRB, and the regulatory authorities may provide direct access 
to the participant’s original medical records. In such cases, the confidentiality of the 
participant should be protected,and by signing and sealing an informed consent form, the 
participant is authorizing such access.
13.If the results of the study are published, the participant’s identity will remain confidential.
14.The anticipated expenses, if any
, to the participant for participating in the study
15.The anticipated prorated payment, if any, to the participant for participating in the study
16.The name, title, and address of the investigator to contact
17.The person(s) to contact for further information regarding the clinical study and the rights of 
participants, and whom to contact in the event of study-related injury
18.The type of the IRB engaged in the assessment and deliberation about the acceptability of the 
study, items subject to the assessment of each IRB, and other IRB-related items relating to 
the study
19.The participant’s responsibilities
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12.3.4
Data Protection
Participants will be assigned a unique identifier by the sponsor. 
Any participant records or 
datasets that are transferred to the sponsorwill contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used bythe 
sponsorin accordance with local data protection law. The level ofdisclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor,by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
12.3.5
Data Quality Assurance
All participantdata relating to the study will be recorded on electronic CRFsunless 
transmitted to the sponsoror designee electronically (eg,laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by electronically signing 
the eCRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered inthe eCRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspectionsandprovidedirect access to source data documents. 
The sponsoror designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICHGCP, and all applicable regulatory requirements. 
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Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator as stated in the clinical trial agreement. No records may be 
destroyed during the retention period withoutthe written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor. 
Source Documents
12.3.6
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFthat are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, dependingon the study.Also,current 
medical records must be available.
12.3.7
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A
 study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator mayinitiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limitedto:
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines
Inadequate recruitment of participants by the investigator
Discontinuation of further study treatment development
12.3.8
Publication Policy
Allergan as the sponsor has proprietary interest in this study. 
Authorship and manuscript 
composition will reflect joint cooperation between the investigator or multiple investigators 
and sites and Allergan personnel. Authorship will be established prior to the writing of the 
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manuscript. As this study involves multiple centers, no individual publications will be 
allowed prior to completion of the final report of the multicenter study except as agreed with 
Allergan.
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In the 
caseof a multicenter study, a coordinating investigator will be designated by mutual 
agreement.
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission. This allows the sponsor to protect proprietary information and to provide 
comments. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
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12.4Appendix 4:Adverse Events: Definitionsand Procedures for Recording, 
Evaluating, Follow-up,and Reporting
Definition of AE
AEDefinition
An AE is any untoward medical occurrence in a patientor clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
NOTE: An AE can therefore be anyunfavorableand unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study treatment.
AE of Special Interest (AESI)
An adverse event of special interest (AESI)(serious or nonserious) is one of scientific 
and medical concern specific to the sponsor’s study drug/device or program, which 
warrants ongoing monitoring and rapid communication by the investigator to the sponsor
. 
Such an event might warrant further investigation in order to characterize and understand 
it.
The following AESIs have been identified for the study interventions in this protocol (see 
also Section 9.2.7):
1.
Hy’s law cases
2.
Inadequate control of diabetes: hyperglycemia and hypoglycemia
3.
MACE
Serious AESIs should be reported to the sponsor within 24 hours via the SAE form. 
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Events Meetingthe AE Definition 
Any abnormal laboratory test results (hematology, clinical chemistry
, or urinalysis) or 
other safety assessments (eg,ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, consideredclinically significant in the 
medical and scientific judgmentof the investigator (ie,not related to progressionof 
underlying disease)
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition
New condition detected or diagnosed after study treatment administration even 
though it may have been present beforethe start of the study
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction
Signs, symptoms, or the clinical sequelae of asuspected overdose of either study 
treatment or a concomitant medication.Overdose per se will not be reported as an 
AE/SAE unless itis an intentional overdose taken with possible suicidal/self-harming 
intent.Such overdosesshould be reported regardlessof sequelae.
Lack of efficacyor failure of expected pharmacological action per se will not be 
reported as an AE or SAE.Such instances will be captured in the efficacy 
assessments.However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacywill be reported as AE or SAEif they fulfilthe definition of an AE or 
SAE.
Events NOT Meeting the AE Definition 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments thatare associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition
The disease/disorder being studied or expected progression, signs, or symptoms
(clearly defined)of the disease/disorder being studied, unless more severe than 
expected for the participant’s condition
The following events are considered to be manifestations of diabetic gastroparesis 
and will be captured in the DGSSS,but will not be reported as AEs or SAEs: nausea, 
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abdominal pain, upper abdominal pain, vomiting, postprandial fullness, bloating, 
early satiety.If the investigator considers these manifestations to have a reasonable 
possibility of relationship to the study drug/device(s) then they should be reported as 
AEs or SAEs
Medical or surgical procedure (eg,endoscopy
, appendectomy): the condition that 
leads to the procedure is theAE
Situations in whichan untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen
Definition of SAE
If an event is not an AE perthedefinition above, then it cannot be an SAE even if serious 
conditions are met (eg,hospitalization for signs/symptoms of the disease under study, death due 
to progression of disease).
AnSAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is lifethreatening
The term lifethreateningin the definition of seriousrefers to an event in which the participant
was at risk of death at the time of the event.It does not refer to an event, which hypothetically 
might have caused death, if it were more severe.
c. Requiresinpatienthospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participanthas been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or outpatient setting.Complications 
that occur during hospitalization are AEs.If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious.When in doubt as to whether hospitalization 
occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d. Results in persistentdisability/incapacity
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The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg,sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption.
e. Is a congenital anomaly/birth defect
f. Other situations:
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
lifethreatening or result in death or hospitalization but may jeopardize the participantor may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition.These events should usuallybe considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that 
do not result in hospitalization, or development of drug dependency or drug abuse.
Recording an AE and/orSAE
AE and SAE Recording
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg,hospital progress notes, laboratoryreports, and diagnostics reports) 
related to the event.
The investigator will then record all relevant AE/SAE information in the eCRF.
It is notacceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsorin lieu of completion of the AE/SAE CRF page.
There may be instances when copies of medical records for certain cases are requested by the 
Sponsor.In this case, all participantidentifiers, with the exception of the participantnumber, 
will be redacted on the copies of the medical records beforesubmission tothe Sponsor.
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information.Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.
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Assessment of Intensity
The investigator will make an assessment of intensity for each 
AE and SAE reported 
during the study and assign it to 1 of the following categories: 
MILD
A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere 
with usual activities of daily living.
MODERATE
A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily 
living, causing discomfort but poses no significant or permanent risk of harm 
to the research participant.
SEVERE
A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention.
An event is defined as seriouswhen it meets at least oneof the predefined outcomes as described 
in the definition of an SAE,NOT when it is rated as severe.
Assessment of Causality
The investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE.
A “reasonable possibility”of a relationship conveysthat there are facts, evidence,and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study treatment administration will be 
considered and investigated.
The investigator will also consult the investigator’sbrochure (IB) and/or product information, 
for marketed products, in his/her assessment.
For each AE/SAE,the investigator mustdocument in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
There may be situations in which an SAE has occurred and the investigator has minimal 
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information to include in the initial report to the Sponsor.However, it is very important that 
the investigator always make an assessment of causality for every event beforethe initial 
transmission of the SAE data to the Sponsor.
The investigator may change his/her opinion of causality in light of follow-up information
and send an SAE follow-up report with the updated causality assessment.
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals
If a participant dies during participation in the study or during a recognized follow-
up period, the investigatorwill provide the Sponsor with a copy of any post-mortem 
findings including histopathology
New or updated information will be recorded in the originally completed eCRF
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information
Reporting of SAEs
SAE Reporting to the Sponsor via e-mail, fax, or telephone
Email is the preferred method for transmission ofSAE information to the Sponsor.
Facsimile transmission ofSAE information is also acceptable. 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable,with a copy of the SAE form sentby overnight mail or 
courier service.
Initial notification via telephone does not replace the need for the investigator to 
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complete and sign the SAE formwithin the designated reporting time frames.
Contacts for SAE reporting can be found in the Study Reference Manual.
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12.5Appendix5: Contraceptive Guidanceand Collection of Pregnancy 
Information
Definitions
Woman of Childbearing Potential (WOCBP)
A
 woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile(see below).
Women in the following categories are not considered WOCBP:
1. Premenarchal 
2. Premenopausal female with 1 of the following:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview
.
3. Postmenopausalfemale
A
 postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A
 high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However,in the absence of 12months of amenorrhea, 
a single FSH measurement is insufficient. 
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HR
T 
during the study
. Otherwise, they must discontinue HR
T to allow confirmation of 
postmenopausal status beforestudy enrollment.
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ContraceptionGuidance
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12.6Appendix 6:Liver Safety:Suggested Actions and Follow-up Assessments
Hy's law cases are considered 
AESIs. Hy’s Law criteria are as follows:
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 × upper limits of 
normal (ULN) 
AND Total bilirubin ≥ 2 × ULN 
AND Alkaline phosphatase < 2 × ULN
Investigational product must be discontinued if any of the following criteria are met:
ALT or AST ≥ 3 ×ULN and the participantis symptomatic with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia (>5%) 
ALT or AST ≥ 3 ×ULN andtotal bilirubin > 2 ×ULN or INR > 1.5 x ULN
ALT or AST ≥ 5 ×ULNfor more than 2 weeks
ALT or AST ≥ 8 ×ULN
The participantmay be re-challenged with study treatment only after consultation with the 
Allergan MSP. For participantswho are not re-challenged with study treatment, the participant 
should be discontinued from the study and complete the Early Termination Visit. Participants 
should receive appropriate follow-up as per standard of care.
Hy’s Law Cases
Sites must report every subject who meets the following Hy’s law criteria if this occurs within 
the time the subject signs the ICF until 30 days after the last dose of study treatment.
A
 laboratory alert for Hy’s laws cases will be in place, and the investigators and 
Allergan will be 
notified immediately when the above criteria have been met. 
Any Hy’s laws case should be 
considered an SAE and also reported as an AE of Special Interest.
Everyeffort to determine the cause of the liver abnormalities 
must be made, and close monitoring should be initiated in conjunction with the Allergan medical 
monitor and in accordance with the FDA
 “Guidance for Industry: Drug Induced Liver Injury -
Pre-Marketing Clinical Evaluation” July2009.
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12.7Appendix7:Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up,and Reporting 
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all sponsor
medical devices provided for use in the study (see Section 7.1for the list of sponsormedical 
devices).
Medical Device Incident Definition
A
 medical device incident isany malfunction or deterioration in the characteristics and/or 
performance of a device as well as any inadequacy in the labellingor the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
participant/user/other person or to a serious deterioration in his/herstate of health.
Not all incidents lead to death or serious deterioration in health.The non-occurrence of such 
a result might have been due to other fortunate circumstances or to the intervention of health 
care personnel.
It is sufficient that:
An incidentassociated with a device happened 
AND
The incidentwas such that, if it occurred again, might lead to death or a serious deterioration 
in health.
A
 serious deterioration in state of health can includeany of the following:
Life-threatening illness
Permanent impairment of body function or permanent damage to body structure
Condition necessitating medical or surgical intervention to prevent one of the above 
Fetal distress, fetal death,or any congenitalabnormality or birth defects
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Examples ofIncidents
Aparticipant, user, caregiver,or healthcare professional is injured as a result of a medical 
device failure or its misuse.
A
 participant’s study treatment is interrupted or compromised by a medical device failure.
A
 misdiagnosis due to medical device failure leads to inappropriate treatment.
Aparticipant’s health deteriorates due to medical device failure.
Documenting Medical Device Incidents
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12.8Appendix 8:Standard Discontinuation Criteria
CDISC Submission Value
CDISC Definition
Adverse event
Any untoward medical occurrence in a patient or 
clinical investigation participant administered a 
pharmaceutical product and which does not 
necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be 
any unintended sign (including an abnormal 
laboratory finding), symptom, or disease 
temporally associated withthe use of a medicinal 
(investigational) product, whether or not related 
to the medicinal (investigational) product. For 
further information, see the ICH Guideline for 
Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting. [Modified 
from ICH E2A] Synonyms: side effect, adverse 
experience. See also serious adverse event, 
serious adverse experience. (CDISC glossary)
Completed
To possess every necessary or normal part or 
component or step; having come or been brought 
to a conclusion (NCI)
Death
The absence of life or state of being dead (NCI)
Failure to meet randomization criteria
An indication that the subject has been unable to 
fulfill/satisfy the criteria required for assignment 
into a randomized group
Lack of efficacy
The lack of expected or desired effect related to a 
therapy (NCI)
Lost to follow-up
The loss or lack of continuation of a subject to 
follow-up
Other
Different than the one(s) previously specified or 
mentioned (NCI)
Investigatordecision
A position, opinion or judgment reached after 
consideration by a physician with reference to 
subject (NCI)
Pregnancy
Pregnancy is the state or condition of having a 
developing embryo or fetus in the body (uterus), 
after union of an ovum and spermatozoon, during 
the period from conception to birth. (NCI)
Protocol deviation
An event or decision that stands in contrast to the 
guidelines set out by the protocol (NCI)
Screen failure
The potential subject who does not meet one or 
more criteria required for participation in a study
Site terminated by sponsor
An indication that a clinical study was stopped at 
a particular site by its sponsor (NCI)
Study terminated by sponsor
An indication that a clinical study was stopped by 
its sponsor(NCI)
Withdrawal by participant
An indication that a study participant has 
removed itself from the study (NCI)
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12.9Appendix 9: Study Tabular Summary
Parameter Group
Parameter
Value
Studyinformation
StudyTitle
A 52-week, Randomized, Double-blind, 
Placebo-controlled, Phase 3 Study to 
Evaluate the Safety and Efficacy of 
Relamorelin in Patients with 
Gastroparesis
Clinical Study Sponsor
Allergan Sales
StudyPhase Classification
Phase 3 Study
StudyIndication
Diabetic gastroparesis
StudyIndication Type
Treatment
StudyType
Efficacy
Safety
StudyLength
Up to 58 weeks, consisting of a 4-week 
Screening Period, 2-week Run-in Period, 
and a 52-week Treatment Period
Planned Country of Investigational Sites
Global
Planned Number of Subjects
Approximately 5000 participants will be 
screened in studies RLM-MD-01 and 
RLM-MD-02. Participants who screen 
fail those studies for certain reasons (see 
below) may enter this study toachieve 
600 participants assigned to study 
treatment (400 to relamorelin and 200 to 
placebo). Atotal of 300 participants are 
expected to complete the study (200 
relamorelin-and 100 placebo-treated
participants).
FDA-Regulated Device Study Indicator
No
FDA-Regulated Drug Study Indicator
No
Pediatric Study Indicator
No
Subject 
information
Diagnosis Group
Diabetesmellitus
Healthy Subject Indicator
No
Planned Minimum Age of Subjects
18
Planned Maximum Age of Subjects
none
Sex of Participants
Both
Stable Disease Minimum Duration
3 months
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Parameter Group
Parameter
Value
Treatments
Investigational Therapy or Treatment
relamorelin
Intervention Type
drug
Pharmacological Class of Invest. Therapy
synthetic ghrelin analogue
Dose per Administration
10 µg
Dose Units
Pre-Filled Cartridge in Multi-dose Pen 
Injector
Dosing Frequency
twice daily
Route of Administration
subcutaneous injection
Current Therapy or Treatment
treatment
Added on to Existing Treatments
No
Control Type
Placebo
Comparative Treatment Name
none
Studydesign
Study Type
Interventional
Intervention Model
Parallel
Planned Number of Arms
2
Studyis Randomized
yes
Randomization Quotient
2 : 1
StudyBlinding Schema
Double-blind
Stratification Factor
Not applicable
Adaptive Design
No
Study Stop Rules
Not stated
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SAP_001.pdf: 
NCT03383146 
 
Study ID: RLM-MD-04 
 
 
Title:  A 52-week, Randomized, Double-blind, Placebo-controlled, Phase 3 Study to Evaluate the Safety 
and Efficacy of Relamorelin in Patients With Diabetic Gastroparesis 
 
Statistical Analysis Plan Amendment 1 Date: 15Dec2020 


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1.0
Title Page
RLM-MD-04
A 52-week, Randomized, Double-blind, Placebo-controlled, Phase 3 Study to Evaluate the 
Safety and Efficacy of Relamorelin in Participants with Diabetic Gastroparesis
STATISTICAL ANALYSIS PLAN - Abbreviated Clinical Study Report
Final: 28 September, 2020
Amendmend #1: 15 December, 2020


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2.0
Table of Contents
1.0
Title Page ........................................................................................................................................................1
2.0
Table of Contents ............................................................................................................................................2
2.1
List of Tables ....................................................................................................................................3
3.0
List of Abbreviations.......................................................................................................................................4
4.0
Introduction.....................................................................................................................................................6
4.1
Study Design.....................................................................................................................................6
Schedule of Activities (SoA).........................................................................................................................................9
5.0
Objectives......................................................................................................................................................13
6.0
Populations for Analyses...............................................................................................................................14
6.1
Screened Population........................................................................................................................14
6.2
Intent-to-Treat Population...............................................................................................................14
6.3
Modified Intent-to-Treat Population...............................................................................................14
6.4
Safety Population............................................................................................................................14
7.0
Participant Disposition ..................................................................................................................................15
8.0
Demographics and Other Baseline Characteristics........................................................................................16
9.0
Extent of Exposure........................................................................................................................................17
10.0
Efficacy Analyses..........................................................................................................................................18
11.0
Safety Analyses.............................................................................................................................................19
11.1
Adverse Events ...............................................................................................................................19
11.2
Clinical Laboratory Parameters.......................................................................................................20
11.3
Vital Signs.......................................................................................................................................22
11.4
Electrocardiogram...........................................................................................................................22
11.5
COVID-19.......................................................................................................................................22
12.0
Interim Analysis ............................................................................................................................................23
13.0
Determination of Sample Size.......................................................................................................................24
14.0
Statistical Software........................................................................................................................................25
15.0
Data Handling Conventions ..........................................................................................................................26
15.1
Analysis Weeks for Efficacy Analysis............................................................................................26
15.2
Derived Efficacy Parameters...........................................................................................................27
15.2.1
Weekly DGSSS ................................................................................................................27
15.3
Visit Time Windows for Safety Analysis .......................................................................................27
15.4
Repeated or Unscheduled Assessments of Safety Parameters ........................................................27
15.5
Missing Date of the Last Dose of Study Treatment ........................................................................27
15.6
Missing Severity Assessment for Adverse Events..........................................................................28
15.7
Missing Date Information for Adverse Events................................................................................28
16.0
Changes to Analyses Specified in Protocol...................................................................................................30


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17.0
References.....................................................................................................................................................31
2.1
List of Tables
Table 11.2–1.
Criteria for Potentially Clinically Significant Laboratory Tests ..............................................21
Table 15.1.1–1
Analysis Week Windows for Efficacy Analysis......................................................................26


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3.0
List of Abbreviations 
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
AST
aspartate aminotransferase
ATC
Anatomical/Therapeutic/Chemical
CDC
Center for Disease Control
CFB
change from baseline
DG
diabetic gastroparesis
DGSSD
Diabetic Gastroparesis Symptom Severity Diary
DGSSS
Diabetic Gastroparesis Symptom Severity Score
eCRF
electronic case report form
ECG
electrocardiogram, electrocardiographic
EOS
end of study
GEBT
gastric emptying breath test
HbA1c
glycosylated hemoglobin A1c
ITT
intent to treat
PCS
potentially clinically significant
PT
Preferred Term
QTc
QT interval corrected for heart rate
QTcB
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)½)
QTcF
QT interval corrected for heart rate using the Fridericia formula (QTcF = QT/(RR)⅓)
RM
rescue medication
RLM
Relamorelin
SAE
serious adverse event
SI
Le Système International d’Unités (International System of Units)
SoA
Schedule of activities
SOC
system organ class
T1DM
type I diabetes mellitus
TBL
total bilirubin
TEAE
treatment-emergent adverse event


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TESAE
treatment-emergent serious adverse event
WOCBP
women of childbearing potential


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4.0
Introduction
The statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data as outlined and specified in the protocol RLM-
MD-04, Amendment 3 (dated 29 Apr 2019).
However, the study was early/prematurely terminated on 04 September 2020 and only an 
abbreviated study report will be applied to this study to report only some safety analyses and 
along with some basic trial characteristics data summaries.
This SAP amendment is based on the SAP dated 28 September 2020. The major change to the 
SAP is to add descriptive analyses for the key efficacy endpoints for the results posting on 
ClinicalTrials.gov and EudraCT (European Union Drug Regulating Authorities Clinical Trials 
Database) and add the COVID-19 data listing.  
4.1
Study Design 
Overall Study Design:

Global, multicenter, randomized, double-blind, placebo-controlled, parallel-group

Treatment Group: Relamorelin 10 μg or placebo subcutaneously twice daily

Study Duration: 52-week Double-blind Treatment Period

Participants who meet study entry and randomization criteria will be randomized in a 
2:1 ratio to blinded treatment with relamorelin 10 µg or placebo, and will use an electronic 
hand-held device for reporting of their symptoms, treatment satisfaction, compliance, and use 
of rescue medication.
Planned enrollment for this study is 600 participants assigned to study treatment (400 to 
relamorelin and 200 to placebo). A total of 300 participants are expected to complete the study 
(200 relamorelin- and 100 placebo-treated participants).
Two different groups of participants may enter into the study, rollover participants and de novo
participants.
1. Rollover participants are those who met all Screening and Run-in Period criteria in 
lead-in Study RLM-MD-01 or lead-in Study RLM-MD-02 (including compliance with 
dosing and data entry into the Diabetic Gastroparesis Symptom Severity Diary 
(DGSSD) during the lead-in study Run-in Period), but were not randomization-eligible 
at the end of the lead-in study Run-in Period. They are eligible for randomization in 
Study RLM-MD-04 if:

They had no vomiting episodes recorded in the DGSSD and had an average daily 
Diabetic Gastroparesis Symptom Severity Score (DGSSS) ≥ 12 at the end of the 
lead-in study Run-in Period.


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OR 

They had vomiting episodes recorded in the DGSSD but had an average daily 
DGSSS of ≥12 and < 16 at the end of the lead-in study Run-in Period. 
Rollover participants will enter the study at Visit 1 (Randomization); they will not undergo 
Screening (Visit –2) or Run-in Visit (Visit –1) procedures.
De novo participants are those who undergo screening and Run-in procedures in Study 
RLM-MD-04. De novo participants are eligible for randomization if they meet all Screening and 
Run-in Period criteria for Study RLM-MD-04, including:
At the Screening Visit (Visit -2):

Male or female aged 18 years and older;

T1DM or T2DM with controlled and stable blood glucose levels and HbA1c 
< 11%;

Symptoms suggestive of DG for at least 3 months (one of which must be 
nausea), with mechanical obstruction of the gastrointestinal tract as the cause of 
symptoms having been ruled out;

History of nausea and/or at most a single episode of vomiting in the 2 weeks 
prior to Screening (Visit -2), as ascertainied by participant history
At the End of the Run-in Period:

Evidence of compliance during the Run-in Period with both the use of the 
electronic hand-held device for entry of data and with twice daily SC injections 
of the study treatment;

No treatment with GI promotility agents during the Run-in Period;

A score of >= 12 for the average of the daily DGSSS measured during the 
Run-in Period.


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Study Schematic:


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Schedule of Activities (SoA)


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5.0
Objectives
Key Objectives
Key Endpoints

To compare the efficacy of relamorelin with that of 
placebo in participants with DG with respect to a 
composite of the following core signs and 
symptoms of DG:
o
Nausea
o
Abdominal pain
o
Postprandial fullness
o
Bloating

Change from baseline to Week 12 in the weekly 
DGSSS

Change from baseline to Week 52 in weekly 
average DGSSS

To compare the safety of relamorelin with that of 
placebo in participants with DG

AEs, clinical laboratory values, vital signs, ECGs, 
HbA1c, and anti-relamorelin antibodies
Other Objectives
Other Endpoints

To assess relamorelin treatment effect on 
individual symptoms of DG such as nausea, 
abdominal pain, bloating, postprandial fullness, 
early satiety, and vomiting frequency

Change from baseline to Week 12 and Week 52 in 
the following:
o
Nausea
o
Abdominal pain
o
Bloating
o
Postprandial fullness
o
Early satiety
o
Vomiting frequency


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6.0
Populations for Analyses
6.1
Screened Population
The Screened Population will consist of all participants who sign informed consent.
6.2
Intent-to-Treat Population
The Intent-to-Treat (ITT) Population will consist of all randomized participants.
6.3
Modified Intent-to-Treat Population
The Modified Intent-to-Treat (mITT) Population will consist of all randomized participants with 
≥1 postbaseline assessment of DGSSD. It is a subset of the ITT Population.
6.4
Safety Population
The Safety Population will consist of all participants who receive ≥ 1 administration of study 
treatment.
The Safety Population will be used for all safety analyses. Participants will be analyzed 
according to the treatment they actually received during the Double-blind Treatment Period. In 
case a participant receives relamorelin 10 μg and placebo alternatively during the study, the 
participant will be included in the relamorelin 10 μg group for purpose of safety analyses.


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7.0
Participant Disposition
The number and percentage of participants screened will be tabulated by de novo participants 
and rollover participants from lead-in studies RLM-MD-01 and RLM-MD-02 for the Screened
Population.
The number and percentage of participants who complete the study and of participants who 
prematurely discontinue will be presented by treatment group and overall for the ITT Population. 
All participants who prematurely discontinue will be listed by discontinuation reason.
The number and percentage with significant protocol deviations will be presented by treatment 
group and overall for the ITT Population.


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8.0
Demographics and Other Baseline Characteristics
Demographic parameters (e.g., age, age group, race, ethnicity, sex, geographic region) will be 
summarized by treatment group and overall for the Safety Population.
Abnormalities in participants’ medical and surgical histories will be coded using the Medical 
Dictionary for Regulatory Activities, version 23.0 or newer. A data listing for medical and 
surgical histories will be presented.   
Prior medication is defined as any medication started before the date of the first dose of double-
blind study treatment. Concomitant medication is defined as any medication taken on or after the 
date of the first dose of double-blind study treatment. 
The WHO Drug Dictionary, Version B2 March 2017 or newer, will be used to classify prior and 
concomitant medications by WHO Drug Anatomical/Therapeutic/Chemical (ATC) category and 
drug preferred name. A data listing for prior and concomitant medications will be presented.   


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9.0
Extent of Exposure 
A listing of the investigational product dosing records will be provided for ITT population.


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10.0
Efficacy Analyses
The main efficacy assessment is the Diabetic Gastroparesis Symptom Severity Diary (DGSSD), 
a 7-item, patient-reported daily diary designed to assess the severity of 6 core signs and 
symptoms of DG—nausea, abdominal pain, postprandial fullness, bloating, vomiting, and early 
satiety—and the frequency of vomiting episodes. The severity of DG symptoms are assessed 
using a 0 to 10 numerical rating scale (NRS), on which 0 = “no” or “not at all uncomfortable” 
(ie, absence of the DG symptom) and 10 = “worst possible” or “most uncomfortable” (ie, worst 
experience of the DG symptom).
The Diabetic Gastroparesis Symptom Severity Score (DGSSS) is an overall assessment of the 
severity of non-vomiting symptoms. It is the sum of the four individual DGSSD items of nausea, 
abdominal pain, postprandial fullness and bloating. The score ranges from 0 to 40. 
Participants report their symptoms daily from Visit 1/Baseline to Visit 4/Week 12, and for each 
of the 4 weeks preceding Visits 5/Week 24, Visit 6/Week 36, and Visit 7/Week 52 in the 
DGSSD. 
Baseline values for DGSSD based parameters are derived from the DGSSD assessment collected 
during the Run-in Period as the average of the two weekly values of Week -2 and Week -1.
There are two key efficacy endpoints as follows:
Key Endpoints
Description
Timing
CFB to Week 12 in 
weekly DGSSS
Change from baseline to Week 12 in weekly 
DGSSS
Week 12
CFB to Week 52 in 
weekly average DGSSS
Change from baseline in average of the 
weekly average DGSSS from Weeks 49 to 52
Week 49-Week 52
Since the study was early terminated, only descriptive analyses for the key efficacy endpoints
will be performed.


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11.0
Safety Analyses
The safety analysis will be performed using the Safety Population. The safety parameters will 
include adverse events (AEs), clinical laboratory, electrocardiogram, vital sign parameters. 
11.1
Adverse Events
All AEs and serious AEs (SAEs) will be collected from the signing of the informed consent form 
(ICF) until 30 days after the final visit in the study (Visit 7) or Early Termination Visit at the 
time points specified in the SoA. For rollover participants, ongoing AEs from lead-in Studies 
RLM-MD-01 and RLM-MD-02, and new AEs that occur after the signing of the ICF for 
RLM-MD-04 are considered to be AEs in RLM-MD-04.
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 23.0 or newer.
An AE will be considered a treatment-emergent adverse event (TEAE) if the AE began or
worsened (increased in severity or became serious) on or after the date of the first dose of 
double-blind study intervention. However, an AE that occurs more than 30 days after the last 
dose of study intervention will not be counted as a TEAE. Per case report form instructions, a 
new AE record will be created with a new AE onset date for any AE that worsens. Therefore,
TEAEs can simply be identified as those AEs with recorded onset date on or after the date of the 
first dose of double-blind study intervention and within 30 days of the last dose of double-blind 
study intervention. 
An AE will be considered a treatment-emergent SAE (TESAE) if it is a TEAE that also is an
SAE. 
The number and percentage of participants with TEAEs, death, TESAE, treatment related TEAE, 
TEAEs leading to treatment discontinuation, and TEAEs leading to discontinuation from study 
will be presented by treatment group.
The number and percentage of participants reporting TEAEs in each treatment group will be 
tabulated by descending percentage in Relamorelin group, by system organ class (SOC), 
preferred term, and severity. If more than 1 AE is coded to the same preferred term for the same 
participant, the participant will be counted only once for that preferred term using the greatest 
severity for the summarization by severity.
The number and percentage of participants reporting treatment-related TEAE, TESAEs, 
treatment related TESAE, and having TEAEs leading to discontinuation of the study in each 
treatment group will be summarized by system organ class and preferred term.
In addition, listings for participants who died, participants with AEs, participants with TESAEs, 
participants with TEAEs leading to discontinuation from study will be presented.


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11.2
Clinical Laboratory Parameters
Clinical laboratory test values from all assessments (including those from unscheduled or repeat 
assessments) will be considered potentially clinically significant (PCS) if they meet either the 
lower-limit or higher-limit PCS criteria listed in Table 11.2–1.
The number and percentage of participants who have PCS post-baseline clinical laboratory 
values will be tabulated by treatment group for the Double-blind Treatment Period. The 
percentages will be calculated relative to the number of participants with available non-PCS 
baseline values and at least 1 post-baseline assessment for the Double-blind Treatment Period. 
The numerator will be the total number of participants with available non-PCS baseline values 
and at least 1 PCS post-baseline value for the Double-blind Treatment Period. 


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Table 11.2–1.
Criteria for Potentially Clinically Significant Laboratory Tests
Parameter
SI Unit
Lower Limit
Higher Limit
CHEMISTRY
Albumin
g/L
< 0.9 * LLN
> 1.1 * ULN
Alanine Aminotransferase 
(ALT)
U/L
—
≥ 3 * ULN
Alkaline Phosphatase
U/L
—
≥ 3 * ULN
Aspartate Aminotransferase 
(AST)
U/L
—
≥ 3 * ULN
Calcium
mmol/L
< 0.9 * LLN
> 1.1 * ULN
Chloride
mmol/L
< 0.9 * LLN
> 1.1 * ULN
Cholesterol
mmol/L
—
> 1.6 * ULN
Creatinine
μmol/L
—
> 1.3 * ULN
Potassium
mmol/L
< 0.9 * LLN
> 2.0 * ULN
Glucose, Fasting
mmol/L
< 0.9 * LLN
> 2.5 * ULN
Glycohemoglobin A1C
%
Increase of ≥ 0.5%
Glycohemoglobin A1C
%
Increase of ≥ 1%
Sodium
mmol/L
< 0.9 * LLN
> 1.1 * ULN
Total Bilirubin
μmol/L
—
> 1.5 * ULN
Total Protein
g/L
< 0.9 * LLN
> 1.1 * ULN
Triglycerides, Fasting
mmol/L
—
≥ 3 * ULN
Urea (BUN)
mmol/L
—
> 1.2 * ULN
Magnesium
mmol/L
< 0.9 * LLN
> 1.1 * ULN
Bicarbonate
mmol/L
< 0.9 * LLN
> 1.1 * ULN
Phosphate
mmol/L
< 0.9 * LLN
> 1.1 * ULN
Uric Acid
μmol/L
< 0.9 * LLN
> 1.1 * ULN
HEMATOLOGY
Basophils Absolute 
Cell Count
109/L
—
> 3 * ULN
Eosinophils Absolute 
Cell Count
109/L
—
> 3 * ULN
Hematocrit
Ratio
< 0.9 * LLN
> 1.1 * ULN
Hemoglobin
g/L
< 0.9 * LLN
> 1.1 * ULN
Lymphocytes Absolute Cell 
Count 
109/L
< 0.8 * LLN
> 1.5 * ULN
MCH
PG
—
> 3 * ULN
MCHC
G/L
—
> 3 * ULN
MCV
fL
< 0.9 * LLN
> 1.1 * ULN
Monocytes Absolute Cell 
Count
109/L
—
> 3 * ULN
Neutrophils Absolute 
Cell Count
109/L
< 0.8 * LLN
> 1.5 * ULN
Platelet Count
109/L
< 0.5 * LLN
> 1.5 * ULN


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RLM-MD-04 Statistical Analysis Plan Amendment #1
Table 11.2–1.
Criteria for Potentially Clinically Significant Laboratory Tests
Parameter
SI Unit
Lower Limit
Higher Limit
Red Blood Cell Count
(Erythrocyte Count)
1012/L
< 0.9 * LLN
> 1.1 * ULN
White Blood Cell Count
109/L
< 0.7 * LLN
> 1.5 * ULN
URINALYSIS
pH
< 0.9 * LLN
> 1.1 * ULN
Specific Gravity
—
> 1.1 * ULN
LLN: Lower limit of normal value provided by the laboratory.
ULN: Upper limit of normal value provided by the laboratory.
11.3
Vital Signs
A listing for vital signs (heart rate (HR), respiratory rate, systolic and diastolic blood pressure
(BP), temperature, and body weight) at each visit will be presented.
11.4
Electrocardiogram
A listing for electrocardiographic(ECG) parameters (HR, RR interval, PR interval, QRS interval, 
QT interval, and QTc) at each assessment time point will be presented. The QTc will be 
calculated using Fridericia and/or Bazett correction.
11.5
COVID-19
A listing of participants with visits impacted due to COVID-19 for the ITT population will be 
provided.


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RLM-MD-04 Statistical Analysis Plan Amendment #1
12.0
Interim Analysis
There is no interim analysis planned for this study.


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13.0
Determination of Sample Size
The study is early terminated; and the original study primary objectives are no longer applicable. 
The original study design of this protocol is for those participants who screen failed either of the
two pivotal registration studies (ie, Studies RLM-MD-01 and RLM-MD-02). The original study 
design was to achieve 600 participants from these screen failures (assuming approximately 
2800 participants will be screened for the two pivotal studies together) who will be randomized 
in a 2:1 ratio (for Relamorelin vs Placebo) to this study. For the originally designed two primary 
endpoints (original protocol dated October 6, 2017, amendments #1 and #2 dated December 20, 
2017 and March 29, 2018, respectively), 600 randomized participants would provide at least
90% power for both the 4-symptom composite DGSSS responder endpoint (assuming a placebo 
rate of 14% and a treatment rate of 35%) and the vomiting responder endpoint (assuming a 
placebo rate of 11% and a treatment rate of 26%). For the redesigned key efficacy endpoint,
change from baseline in 4-symptom DGSSS composite score at Week 12 (Protocol amendment 
#3 dated April 29, 2019), the planned sample size of 600 participants would provide more than 
90% power in detecting a clinical meaningful difference, assuming Relamorelin provides
additional 3.8 points of improvement as compared to Placebo. 


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RLM-MD-04 Statistical Analysis Plan Amendment #1
14.0
Statistical Software
Statistical analyses will be performed using version 9.4 (or newer) of SAS on a Linux operating 
system.


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RLM-MD-04 Statistical Analysis Plan Amendment #1
15.0
Data Handling Conventions
15.1
Analysis Weeks for Efficacy Analysis
Table below presents the analysis weeks assigned for the efficacy analysis of the participant
daily diary data related to DGSSD. 
Table 15.1.1–1
Analysis Week Windows for Efficacy Analysis
Period
Analysis Week
Beginsa
Endsa
Pretreatment 
(Baselineb) 
Week -2 
Day -14 
Day -8
Week -1 
Day -7
Day -1
Treatment 
Week 1 
Day 1, day of randomization
Day 7
Week 2 
Day 8
Day 14
Week 3 
Day 15
Day 21
Week 4 
Day 22
Day 28
Week 5 
Day 29
Day 35
Week 6 
Day 36
Day 42
Week 7 
Day 43
Day 49
Week 8 
Day 50
Day 56
Week 9 
Day 57
Day 63
Week 10
Day 64
Day 70
Week 11 
Day 71
Day 77
Week 12 
Day 78
Day 84
Week 21 
Day 141
Day 147
Week 22 
Day 148 
Day 154
Week 23 
Day 155
Day 161 
Week 24
Day 162
Day 168
Week 33
Day 225
Day 231
Week 34
Day 232
Day 238
Week 35
Day 239
Day 245
Week 36
Day 246
Day 252
Week 49
Day 337
Day 343
Week 50
Day 344
Day 350
Week 51
Day 351
Day 357
Week 52
Day 358
Day 364
a
Relative to the date of randomization; Day 1 = the day of randomization. 
b
Baseline values for efficacy parameters will be derived as average of the two pretreatment weeks.
For the Double-blind Treatment Period, diary day is calculated as (diary date - date of 
randomization + 1). For the Pretreatment Period, diary day is calculated as (diary date - date of 
randomization).


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15.2
Derived Efficacy Parameters
15.2.1
Weekly DGSSS 
Weekly scores for nausea, abdominal pain, postprandial fullness, bloating, and vomiting severity 
will be the average of the corresponding nonmissing daily scores if a participant has at least 4 
nonmissing daily scores during a week (See section 15.115.1 for definition of analysis weeks).
Weekly score will be set to missing if there are less than 4 days with nonmissing diary data 
during a week.
Weekly DGSSS is derived as the sum of the weekly DGSSD items of nausea, abdominal pain, 
postprandial fullness, and bloating. The range of DGSSS is from 0 to 40 with 40 indicating the 
worst possible. If any one of weekly items of nausea, abdominal pain, postprandial fullness, and 
bloating is missing, then the weekly DGSSS will be set to missing.
If any of the weekly values during the Run-in Period (Week -2 and/or Week -1) is missing, 
baseline for the DGSSD items (nausea, abdominal pain, postprandial fullness, bloating, and 
vomiting severity) will be the average of the scores reported during the seven days -consecutive 
or not- preceding Day 1.
The Week 52 weekly average DGSSS is the average of the weekly DGSSS from Weeks 49 to 52.
15.3
Visit Time Windows for Safety Analysis
No analysis visit window is needed for safety parameters. The nominal visit or eCRF visit will 
be used for listings.
15.4
Repeated or Unscheduled Assessments of Safety Parameters
If a participant has repeated assessments before the start of double-blind treatment with 
investigational product, the results from the final assessment made before the date of the first 
dose will be used as baseline. 
However, all post-baseline assessments will be used for PCS value determination, and all 
assessments will be presented in the data listings.
15.5
Missing Date of the Last Dose of Study Treatment
When the date of the last dose of the double-blind investigational product is missing, all efforts
should be made to obtain the date from the Investigator. If it is still missing after all efforts have 
been made, the last diary date will be used as the last dose date.


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RLM-MD-04 Statistical Analysis Plan Amendment #1
15.6
Missing Severity Assessment for Adverse Events
If severity is missing for an AE that started before the date of the first dose of double-blind 
investigational product, an intensity of mild will be assigned. If severity is missing for an AE that 
started on or after the date of the first dose of double-blind investigational product, an intensity 
of severe will be assigned. The imputed values for severity assessment will be used for the 
incidence summary; the values will be shown as missing in the data listings.
15.7
Missing Date Information for Adverse Events
The following imputation rules apply to cases in which the start date is incomplete (ie, partial 
missing) for AEs.
Missing day and month

If the year is the same as the year of the date of the first dose of double-blind 
investigational product, then the day and month of the date of the first dose of 
double-blind investigational product will be assigned to the missing fields.

If the year is prior to the year of the date of the first dose of double-blind investigational 
product, then December 31 will be assigned to the missing fields.

If the year is after the year of the date of the first dose of double-blind investigational 
product, then January 1 will be assigned to the missing fields.
Missing month only

The day will be treated as missing and both month and day will be replaced according to 
the above procedure.
Missing day only

If the month and year are the same as the month and year of the date of the first dose of 
double-blind investigational product, then the date of the first dose of double-blind 
investigational product will be assigned to the missing day.

If either the year is before the year of the date of the first dose of double-blind 
investigational product or if both years are the same but the month is before the month of 
the date of the first dose of double-blind investigational product, then the last day of the 
month will be assigned to the missing day.

If either the year is after the year of the date of the first dose of double-blind 
investigational product or if both years are the same but the month is after the month of 
the date of the first dose of double-blind investigational product, then the first day of the 
month will be assigned to the missing day.
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date.


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RLM-MD-04 Statistical Analysis Plan Amendment #1
If the start date is completely missing and the stop date is complete, then the following algorithm 
is used to impute the start date:

If the stop date is on or after the date of the first dose of double-blind investigational 
product, the date of the first dose of double-blind investigational product will be assigned 
to the missing start date.

If the stop date is before the date of the first dose of double-blind investigational product, 
the stop date will be assigned to the missing start date.  


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RLM-MD-04 Statistical Analysis Plan Amendment #1
16.0
Changes to Analyses Specified in Protocol
The study was early terminated and only an abbreviated study report will be applied to this 
study, for which only minimum efficacy analyses will be implemented. As such, this document 
is an abbreviated statistical analysis plan for only selected study disposition, demographics,
safety parameters and selected descriptive efficacy analyses.


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RLM-MD-04 Statistical Analysis Plan Amendment #1
17.0
References
There are no references.


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