Clinical trial NCT03285308
Conditions: Gastroparesis Diabetes Mellitus
Sponsor: Allergan
Start date: 2017-09-29; Completion date: 2020-07-08
Enrollment: 336 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety and efficacy of relamorelin compared to placebo in participants with diabetic gastroparesis. Participants will report daily severity scores of their diabetic gastroparesis symptoms.

Detailed description:

Arms: arm 1: Following a 2-week placebo run-in, participants received placebo-matching relamorelin injected subcutaneously twice daily for up to 12 weeks. arm 2: Following a 2-week placebo run-in, participants received relamorelin 10 μg injected subcutaneously twice daily for up to 12 weeks.
Interventions: intervention 1: Placebo intervention 2: Relamorelin
Intervention descriptions: intervention 1: Placebo injected subcutaneously twice daily. intervention 2: Relamorelin 10 micrograms (μg) injected subcutaneously twice daily.

Protocol documents:
Prot_000.pdf: 
NCT03285308 
 
Study ID: RLM‐MD‐01 
 
 
Title:  A 12‐week, Randomized, Double‐blind, Placebo‐controlled, Phase 3 Study to Evaluate the Safety 
and Efficacy of Relamorelin in Patients with Diabetic Gastroparesis 
 
 
Protocol Amendment 4 Date: 08Feb2019 


Protocol RLM-MD-01, Amendment 4
Relamorelin
1
Title Page
Protocol Title: A 12-week, Randomized, Double-blind, Placebo-controlled, Phase 3 Study to 
Evaluate the Safety and Efficacy of Relamorelin in Patients with Diabetic Gastroparesis
Brief Protocol Title: Diabetic Gastroparesis Study 1
Protocol Number: RLM-MD-01
Amendment Number: 4
Product: Relamorelin
Sponsor Name and Legal Registered Address:
Allergan Sales, LLC, 5 Giralda Farms, Madison, New Jersey 07940, United States
Allergan Ltd., Marlow International, Parkway, Marlow SL7 1YL, United Kingdom
Regulatory Agency Identifying Number(s):
IND: 
EudraCT: 2017-002136-163
Emergency Telephone Number: Refer to study contacts list
Serious Adverse Event Reporting Email/Fax Number:
Allergan Medical Safety Physician: Refer to study contacts list
Approval Date: 08 Feb 2019
Allergan Signatory: 
 Vice President, Clinical Development-GI
03MAR2021 Abbreviated CSR RLM-MD-01
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Protocol RLM-MD-01, Amendment 4
Relamorelin
2
Protocol Amendment 4 Summary of Changes
DOCUMENT HISTORY
Document
Date
Amendment 3
25 Mar 2018
Amendment 2
18 Jan 2018
Amendment 1
17 Sep 2017
Original Protocol
13 Jul 2017
Amendment 4 (08 Feb 2019)
Overall Rationale for Amendment 4:
This summary includes changes made to Protocol RLM-MD-01 from Protocol Amendment 3 
(dated 25 Mar 2018; details provided in Section 12.19). The purpose of Protocol Amendment 4 is 
to communicate changes made in response to recommendations from health authorities. These 
changes will not impact the safety assessment of relamorelin or alter the risk-benefit ratio for 
study participants.
The following is a summary of content-oriented changes that were made. Strikethrough text 
denotes text removed and bolded text denotes added text. Additional administrative edits were 
also made, but not specifically noted (eg, corrected spelling, punctuation, grammar, abbreviation, 
and style errors) including global edits required for consistency.
03MAR2021 Abbreviated CSR RLM-MD-01
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Protocol RLM-MD-01, Amendment 4
Relamorelin
3
Section Number
Description of Change
Rationale
Section 1 Synopsis and 
Section 4 Objectives and 
Endpoints
Modified definition of primary endpoints: 
The Diabetic Gastroparesis Symptom Severity Score (DGSSS) Responder, 
defined as a participant who has a ≥ 10-point improvement in the DGSSS 
compared to baseline in each of the last 6 weeks of the 12-week Treatment 
Period. Change from Baseline to Week 12 in the weekly DGSSS. 
Baseline is defined as the average of the 2 weekly DGSSS from the 2-
week, placebo Run-in Period
Vomiting Responder, defined as a participant with zero weekly who 
reports no vomiting episodes during each of the last 6 weeks of the 12-
week Treatment Period
Change in definition of the primary endpoint 
related to DGSSS; clarification of definition of 
the primary endpoint related to vomiting episodes
Section 1 Synopsis, 
Section 5.2 Participant and 
Study Completion, 
Section 12.9/Appendix 9 
Study Tabular Summary
Increased the number of sites from approximately 200 to approximately 
350
Increased the number of participants screened from 2000 to 2500
To allow for additional sites
To increase the number of potential participants 
who qualify to be randomized
Section 1 Synopsis and 
Section 5.1 Overall Design

Added requirement for study population at screening to have had a 
history of at least 2 vomiting episodes and to have had at least 1 
vomiting episode during the Run-in Period.

Removed BMI information

Changed to clarify that history of vomiting 
episodes and GEBT should be noted in the 
Run-in Period and not the Screening Period

Amended to reflect removal of Inclusion 
Criterion #9
Section 2 SOA, 
Section 1 Synopsis Figure 1 
and Section 5.1 Overall 
Design Figure 2
Start of Screening Period revised form Day -28 to Day -42. Increased 
duration of screening visit from 14 days to 28 days. Updated study 
schematic to reflect the change in length of screening visit
Length of Screening Period increased to allow 
more time for completion of endoscopy or upper 
GI series with contrast and for washout of 
prohibited medications.
Section 1 Synopsis and 
Section 5.1 Overall Design
Increased duration of study from 16 weeks to 18 weeks and increased 
Screening Period from 2 weeks to up to 4 weeks.
To align with change in the length of the 
Screening Period as described above
Section 2 SOA
Addition of footnote (a) for Screening Visit: Results from assessments 
done at Visit 1 (Screening) that might result in exclusion from the study 
should be obtained prior to endoscopy if done between Visit 1 and Visit 2 
(Start of Run-in Period)
To provide details regarding additional 
requirements with the increased length of the 
Screening Period
Section 2 SOA
Added ECG obtained at Visit 4
To meet recommendations made by MHRA and 
ANSM in their review of the protocol-
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Protocol RLM-MD-01, Amendment 4
Relamorelin
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Section Number
Description of Change
Rationale
Section 2 SOA
Amended footnote (j)
To align with changes made to Exclusion Criteria 
#12
Section 2 SOA, 
Section 9.4.6 Self-
monitoring of Blood 
Glucose, Section 12.2 
Table 12-1 Protocol-
Required Safety Laboratory 
Assessments
Removed assessment of glycated albumin from SOA and all related text 
in Section 9.4.6 and Section 12.2 Table 12-1
Preliminary results do not show that assessment 
of glycated albumin is useful for the adjustment 
of glycemic control.
Section 12.2 Table 12-1 
Protocol-Required Safety 
Laboratory Assessments
Added footnote for fasting blood glucose: Serum for all visits except for 
Visit 4 and 6 (plasma)
For clarification
Section 3.2 and 3.3
Removed year in all references to the relamorelin Investigator Brochure 
To align with new Allergan style guide
Section 4 Objectives and 
Endpoints
Amended Clinical Hypotheses
To align with change in primary endpoint
Section 6.1 Inclusion 
Criteria

Amended Inclusion Criterion #6 to allow for a GI series with 
contrast as an assessment tool for documenting absence of an 
obstructing lesion and adjust timing of assessments from some time 
before screening (Visit 1) to sometime before the Run-in Period 
(Visit 2).

Removed BMI criterion #9

Inclusion Criterion #10: added a reference to Appendix 3

To clarify what an acceptable alternative to 
upper endoscopy is for exclusion of an 
obstructing lesion (upper GI series with 
contrast) and to allow either procedure to be 
done during the Screening Period if not done 
previously

BMI not relevant for treatment of 
gastroparesis

To clearly comply with country-specific 
guidelines in the CPT
03MAR2021 Abbreviated CSR RLM-MD-01
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Protocol RLM-MD-01, Amendment 4
Relamorelin
5
Section Number
Description of Change
Rationale
Section 6.2 Exclusion 
Criteria

Amended Exclusion Criterion #3 to specify that participants with 
active eating disorders at the time of screening are to be excluded, as 
opposed to those with a history of eating disorders

Exclusion Criterion #11:  Added 5HT agonists as exclusionary drug.

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; 
specified that opioids are not drugs for which the investigator may 
choose not to consider exclusionary.

Added exclusion criteria for hypersensitivity to the study treatments 
and their excipients (Exclusion Criterion #25) and for specific 
corrected ECG results (Exclusion Criterion #26).

For clarification

Added because 5HT agonists are still 
approved in some countries

To verify that positive urine drug screen 
results are not false-positive before excluding 
a participant from continuing in screening 
and clarify that use of opioids is 
exclusionary.

To meet recommendation made by MHRA in 
its review of the protocols
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.
To verify that positive urine drug screen results 
are not false-positive before excluding a 
participant from continuing in screening, and to 
clarify that the use of barbiturates, 
benzodiazepines and amphetamines are allowable 
if prescribed for continuous use for a clinically 
appropriate indication
Section 7.1 Treatments 
Administered

Clarified that the first dose of study treatment is to be administered 
within approximately 30 minutes before the morning meal and the 
second daily dose is to be administered within approximately 
30 minutes before the evening meal.

Deleted option for investigator to contact sponsor if the participant 
could not inject study treatment into abdomen.
To clarify the timing of dosing and to be 
consistent with the wording in the ICF. Option to 
contact the sponsor removed as the sponsor does 
not currently have any information to support 
injection into alternative sites.
Section 7.4 Blinding
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.
To meet recommendation made by MHRA in its 
review of the protocols, but applicable globally
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Protocol RLM-MD-01, Amendment 4
Relamorelin
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Section Number
Description of Change
Rationale
Section 7.7.1 Prohibited 
Treatments

SGLT-1 added as an exception to prohibited drugs along with 
SLGT-2; specified that SGLT-1 and SGLT-2 inhibitors are 
prohibited for 3 days prior to the GEBT performed at the start of the 
Run-in Period for all participants and for a subset of participants at 
Visit 7 or Early Termination Visit at a subset of sites.

Table 7-2: Corresponding changes as per above; rearranged rows by 
washout period; specified 3 consecutive weeks or more to clarify that 
once weekly requirements of anti-emetics for this amount of time is 
prohibitory; added row for 5HT4 agonists; added tramadol as an 
example of an opioid amended washout period for opioids from 
“10 days prior to the start of the Run-in Period” to Not applicable 
since the use of opioids is not allowed and referenced Exclusion 
Criteria #12 and #13 accordingly.

To clarify that the SGLT-1 or SGLT-2 
inhibitors are prohibited only 3 days prior to 
GEBT as they may affect interpretation of 
the test, but are otherwise allowed

In response to FDA request for more 
definitive direction to investigators regarding 
contacting the sponsor to discuss the 
advisability of continued participation in the 
study by a patient needing frequent anti-
emetic treatment; Tramadol added as an 
example; 5H4T agonists added since they are 
still approved in some countries; aligned with 
exclusion criteria.
Section 7.7.3 Rescue 
Medicine
Clarifications made to text; Removed antihistamines as an example of an 
anti-emetic drug

Requested by FDA as described above

Removed antihistamines as an example of an 
anti-emetic drug as there is no clear evidence 
that they have anti-emetic benefits in the 
context of vomiting and nausea associated 
with DG
Section 8 
Discontinuation/Withdrawal 
Criteria
Removed: “non-compliance with study treatment”
Non-compliance minimum criterion is not 
defined for this protocol
Section 8.1.1 Temporary 
Discontinuation
Added requirement for the investigator to contact the sponsor under 
specific conditions.
In response to FDA request to include 
standardized criteria for restarting study 
treatment, including proposed dose adjustments
Section 9.1 Efficacy 
Assessments
Defined zero and 10 scores of the DG assessments.
To align with the change in the primary endpoint 
and updates made to the SAP in response to FDA 
request
Section 9.1.1.1 Primary 
Efficacy Assessments
Changed Section 9.1.1.1 from DGSSS Responder definition to Change 
from Baseline to Week 12 in the Weekly DGSSS:
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Protocol RLM-MD-01, Amendment 4
Relamorelin
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Section Number
Description of Change
Rationale
Section 9.2.7.1 Hy’s Law
Editorial changes for clarity.
For clarification and to align with changes made 
in Appendix 4
Section 9.2.7.2 Inadequate 
control of diabetes: 
Hyperglycemia and 
Hypoglycemia
Editorial changes to the title for clarity
To keep consistent with the MSMP language
Section 9.2.8 Medication 
Overdose
Text revised for clarity
For clarification
Section 10.1 Sample Size 
Determination
Revised and clarified sample size determination
To align with updated SAP: sample size 
calculations based on the CFB to Week 12
Table 10-2 Statistical 
Methodology
Added a row to describe Change from Baseline (CFB)
For clarification and to align with updated 
endpoints
Table 10-3 Primary and 
Secondary Endpoints
Updated primary endpoint and its description.
To align with change in primary endpoint
Section 10.3.2.2 Multiple 
Comparisons Procedure
Clarifications made to Hypothesis H1; reference made to SAP for other 
efficacy analyses.
To align with change in primary endpoint
Section 10.3.2.3
Updated how missing data will be handled.
To align with updated SAP
Section 10.3.5 Interim 
Analyses and Section 12.3 
Appendix 3 Study 
Governance Consideration
Added a requirement for a DSMB to review interim safety data at defined 
intervals throughout the study.
As requested by health authorities including FDA 
and National Agency for the Safety of Medicine 
and Health Products (ANSM)
03MAR2021 Abbreviated CSR RLM-MD-01
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Protocol RLM-MD-01, Amendment 4
Relamorelin
8
Section Number
Description of Change
Rationale
Section 12.4 Appendix 4 
AE Definitions
Revised procedures for reporting AESIs; specified that specific DG 
manifestations will be captured in the DGSSS and not in the eCRF as a 
complication of the disease, as originally specified.
Provided AESIs that have been identified for relamorelin
To correct an error in how AESIs of should be 
reported based on current Allergan practice
To align with current Allergan practice and the 
Common Protocol Template
Section 12.5 Appendix 5: 
Contraceptive Guidance and 
Collection of Pregnancy 
Information
Deleted footnote b
Per information provided in the IB, the potential 
for relamorelin to inhibit the metabolism of 
concomitantly administered drug is weak. 
Footnote was removed to aligned with IB 
information.
Section 12.8 Appendix 8: 
Standard Discontinuation 
Criteria
Removed criteria for non-compliance
Not applicable to this protocol as participants are 
not discontinued due to non-compliance
03MAR2021 Abbreviated CSR RLM-MD-01
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Protocol RLM-MD-01, Amendment 4
Relamorelin
9
Table of Contents
Title Page .........................................................................................................................................1
Protocol Amendment 4 Summary of Changes.................................................................................2
Table of Contents.............................................................................................................................9
List of Tables .................................................................................................................................12
List of Figures................................................................................................................................12
1.
Synopsis..........................................................................................................................13
2.
Schedule of Activities (SoA) ..........................................................................................17
3.
Introduction.....................................................................................................................21
3.1.
Study Rationale...............................................................................................................22
3.2.
Background.....................................................................................................................23
3.3.
Benefit/Risk Assessment ................................................................................................24
4.
Objectives and Endpoints ...............................................................................................25
5.
Study Design...................................................................................................................26
5.1.
Overall Design ................................................................................................................26
5.2.
Participant and Study Completion ..................................................................................28
5.3.
End of Study Definition..................................................................................................28
5.4.
Scientific Rationale for Study Design ............................................................................28
5.5.
Justification for Dose......................................................................................................29
6.
Study Population.............................................................................................................29
6.1.
Inclusion Criteria ............................................................................................................30
6.2.
Exclusion Criteria ...........................................................................................................31
6.3.
Lifestyle Restrictions......................................................................................................33
6.4.
Screen Failures................................................................................................................34
7.
Treatments ......................................................................................................................34
7.1.
Treatments Administered................................................................................................35
7.1.1.
Run-in Medications and Administration.........................................................................36
7.1.2.
Study Supplies ................................................................................................................36
7.2.
Dose Modification ..........................................................................................................37
7.3.
Method of Treatment Assignment ..................................................................................37
7.4.
Blinding ..........................................................................................................................37
7.5.
Preparation/Handling/Storage/Accountability................................................................38
7.6.
Treatment Compliance....................................................................................................38
7.7.
Concomitant Therapy .....................................................................................................38
7.7.1.
Prohibited Treatments.....................................................................................................39
7.7.2.
Permitted Treatments......................................................................................................40
7.7.3.
Rescue Medicine.............................................................................................................40
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Protocol RLM-MD-01, Amendment 4
Relamorelin
10
7.8.
Treatment after the End of the Study..............................................................................40
8.
Discontinuation/Withdrawal Criteria..............................................................................41
8.1.
Discontinuation of Study Treatment...............................................................................42
8.1.1.
Temporary Discontinuation ............................................................................................42
8.2.
Withdrawal from the Study.............................................................................................42
8.3.
Lost to Follow Up...........................................................................................................43
9.
Study Assessments and Procedures ................................................................................43
9.1.
Efficacy Assessments .....................................................................................................44
9.1.1.
Primary Efficacy Assessments........................................................................................44
9.1.2.
Secondary Efficacy Assessment .....................................................................................45
9.2.
Adverse Events ...............................................................................................................50
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................50
9.2.2.
Method of Detecting AEs and SAEs ..............................................................................50
9.2.3.
Follow-up of AEs and SAEs...........................................................................................51
9.2.4.
Regulatory Reporting Requirements for SAEs...............................................................51
9.2.5.
Pregnancy........................................................................................................................51
9.2.6.
Medical Device Incidents (Including Malfunctions) ......................................................51
9.2.7.
Adverse Events of Special Interest .................................................................................53
9.2.8.
Medication Errors ...........................................................................................................54
9.3.
Treatment of Overdose ...................................................................................................55
9.4.
Safety Assessments.........................................................................................................55
9.4.1.
Physical Examinations....................................................................................................55
9.4.2.
Vital Signs.......................................................................................................................55
9.4.3.
Electrocardiograms .........................................................................................................56
9.4.4.
Clinical Safety Laboratory Assessments ........................................................................56
9.4.5.
Hormonal Assessments...................................................................................................56
9.4.6.
Self-monitoring of Blood Glucose..................................................................................57
9.5.
Pharmacokinetics............................................................................................................57
9.6.
Pharmacodynamics .........................................................................................................57
9.7.
Genetics ..........................................................................................................................58
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Protocol RLM-MD-01, Amendment 4
Relamorelin
11
10.
Statistical Considerations................................................................................................60
10.1.
Sample Size Determination ............................................................................................60
10.2.
Populations for Analyses ................................................................................................60
10.3.
Statistical Analyses .........................................................................................................60
10.3.1.
Key Statistical Methodology...........................................................................................61
10.3.2.
Efficacy Analyses ...........................................................................................................62
10.3.3.
Safety Analyses...............................................................................................................63
10.3.5.
Interim Analyses .............................................................................................................64
11.
References.......................................................................................................................65
12.
Appendices......................................................................................................................68
12.1.
Appendix 1: Abbreviations.............................................................................................69
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Protocol RLM-MD-01, Amendment 4
Relamorelin
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List of Tables
Table 7-1:
Study Treatment Details....................................................................................36
Table 7-2: 
Prohibited Medications and Washout Requirements ........................................39
Table 10-1:
Analysis Populations .........................................................................................60
Table 10-2:
Statistical Methodology.....................................................................................61
Table 10-3:
Primary and Secondary Endpoints ....................................................................62
List of Figures
Figure 1:
RLM-MD-01 Study Schematic .........................................................................15
Figure 2:
RLM-MD-01 Study Schematic .........................................................................27
03MAR2021 Abbreviated CSR RLM-MD-01
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Protocol RLM-MD-01, Amendment 4
Relamorelin
13
1.
Synopsis
Protocol Title: A 12-week, Randomized, Double-blind, Placebo-controlled, Phase 3 Study to 
Evaluate the Safety and Efficacy of Relamorelin in Patients with Diabetic Gastroparesis
Brief Title: Diabetic Gastroparesis Study 1
Study Phase: 3
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, 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 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, and specifically in Study RLM-MD-01.
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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Protocol RLM-MD-01, Amendment 4
Relamorelin
14
Objectives and Endpoints:
Objectives
Endpoints
Primary

To compare the efficacy of relamorelin with 
placebo in participants with DG with respect to a 
composite of the following core signs and 
symptoms of DG:

Nausea

Abdominal pain

Postprandial fullness 

Bloating

Change from Baseline to Week 12 in the weekly 
DGSSS. Baseline is defined as the average of the 2 
weekly DGSSS from the 2-week, placebo Run-in 
Period

To compare the efficacy of relamorelin with placebo 
in participants with DG with respect to vomiting 
frequency

Vomiting Responder, defined as a participant with 
zero weekly vomiting episodes during each of the 
last 6 weeks of the 12-week Treatment Period
Secondary

To compare the efficacy of relamorelin with placebo 
in participants with DG with respect to the 
following individual symptoms of the DGSSS:

Nausea

Abdominal Pain

Postprandial fullness

Bloating

To compare the safety of relamorelin with placebo 
in participants with DG
Secondary

Individual Symptom (ie, nausea, abdominal pain, 
postprandial fullness, and bloating) Responder, 
defined as a participant with at least a 2-point 
decrease in the change from baseline on the weekly 
average of the symptom severity (at its worst) 
during each of the last 6 weeks of the 12-week 
Treatment Period 

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 Groups: Relamorelin 10 μg or placebo subcutaneously (SC) twice daily (BID), 

Study Duration: up to 18 weeks, including a Screening Period of up to 4 weeks, a 2-week 
Run-in Period, and a 12-week Treatment Period: 
o
Run-in Period: Participants who meet initial study entry criteria during the Screening 
Period will enter a 2-week Run-in Period, during which they will self-administer 
placebo twice daily SC. Using an electronic hand-held device, participants will report 
their symptoms via the Diabetic Gastroparesis Symptom Severity Diary (DGSSD) as 
well as their 
 compliance, 
and use of rescue medication. 
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Protocol RLM-MD-01, Amendment 4
Relamorelin
15
o
12-week Treatment Period: Participants who meet study entry criteria at the end of the 
Run-in Period, will be randomized 1:1 to blinded treatment with relamorelin 10 µg or 
placebo, and will continue to use the electronic hand-held device for reporting of their 
symptoms via the DGSSD as well as their 
 
 compliance, and use of rescue medication.
Assuming they meet entry criteria, participants who successfully complete this study are eligible, 
to enter a placebo-controlled, long-term safety and efficacy study (Study RLM-MD-03) during 
which they will receive study treatment for an additional 46 weeks.
Figure 1:
RLM-MD-01 Study Schematic
Number of Participants:
Approximately 2500 participants will be screened to achieve 600 participants randomly assigned
to study treatment (300 per treatment group). A total of 480 participants are expected to complete 
the study (240 per treatment group).
Study Population:

Screening: Males and females aged 18 years and older with T1DM or T2DM with 
controlled and stable blood glucose levels and HbA1c ≤ 11%; symptoms suggestive of 
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Protocol RLM-MD-01, Amendment 4
Relamorelin
16
DG for at least 3 months, with mechanical obstruction of the gastrointestinal (GI) tract as 
the cause of symptoms having been ruled out; history of at least 2 vomiting episodes 

During the Run-in Period: At least 1 vomiting episode and delayed GE by gastric 
emptying breath test (GEBT)

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, no treatment with GI promotility agents during the Run-in Period, at 
least 1 vomiting episode reported during the 2-week Run-in Period, and a score of ≥16 
for the average of the daily Diabetic Gastroparesis Symptom Severity Score (DGSSS)
assessments measured during the Run-in Period.
Number of Sites:
Approximately 350 sites (globally)
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Protocol RLM-MD-01, Amendment 4
Relamorelin
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2.
Schedule of Activities (SoA)
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Protocol RLM-MD-01, Amendment 4
Relamorelin
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Protocol RLM-MD-01, Amendment 4
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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-acid peptide, 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 characterised by 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 (T1DM/T2DM), is considered to 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, post-prandial 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, have a 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 
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. 
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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 unpredictable 
times (Rayner et al, 2001). As a result, diabetic patients with DG often have poorly controlled 
diabetes, frequently with alternating hypo- and hyperglycaemia, 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) showed prevalence 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 (Jung 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 30% to 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 
(Hopkins Medicine, 2013). According to Bharucha (2015), in a restricted community-based 
study of GP in DM, 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 participants 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, 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 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, and specifically in Study RLM-MD-01. 
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 
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suboptimal; therefore, the sponsor is performing this study to further the development of 
relamorelin for the treatment of DG.
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.
In clinical studies to date, 466 participants with T1DM or T2DM with DG have been exposed to 
relamorelin at doses up to 100 μg administered twice daily (BID) by subcutaneous (SC) injection 
for 12 weeks. 
In a randomized, placebo-controlled, multiple-dose Phase 2a study (RM-131-004), participants 
with T1DM and 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 participants with 
vomiting at baseline and 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 patient population for 
enrolment in the Phase 2b Study RM-131-009, DG patients with vomiting at baseline, and 
encouraged assessment of a wider range of relamorelin doses.
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 with T1DM 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 10 µg and 30 µg doses. Vomiting 
frequency was 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 
relamorelin effect that 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 tolerated among participants with T1DM or T2DM and 
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 
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and relamorelin 100 μg groups only). Twenty-three serious adverse events (SAEs) were reported 
in the 289 participants treated with the 3 doses of relamorelin 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 2 of 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. Three adverse events (AEs) of diabetic 
ketoacidosis were reported, 1 event on each relamorelin dose. A total of 20 relamorelin-treated 
participants and 3 placebo-treated participants discontinued study treatment because of a 
treatment-emergent AE; only 3 in the relamorelin10 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 
haemoglobin A1c (HbA1c) values after the initiation of relamorelin, which increased slightly
after 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).
3.3.
Benefit/Risk Assessment
Based on information about relamorelin obtained to date, the benefits of study participation are 
expected to include accelerated GE and clinically meaningful improvement in the symptoms of 
DG, including nausea, abdominal pain, postprandial fullness, bloating, vomiting frequency, 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. See Section 5 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 are provided in the investigator’s brochure 
(Relamorelin Investigator’s Brochure); information about the investigational directions for use 
(DFU) for the pen injector, the device that will be used to administer study treatment are also 
provided.
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4.
Objectives and Endpoints
Objectives
Endpoints
Primary
Primary
To compare the efficacy of relamorelin with 
placebo in participants with DG with respect to a 
composite of the following core signs and 
symptoms of DG:

Nausea

Abdominal pain

Postprandial fullness 

Bloating
Change from Baseline to Week 12 in the weekly 
DGSSS. Baseline is defined as the average of the 
2 weekly DGSSS from the 2-week, placebo Run-in 
Period

To compare the efficacy of relamorelin with placebo 
in participants with DG with respect to vomiting 
frequency
Vomiting Responder, defined as a participant with zero 
weekly vomiting episodes during each of the last 
6 weeks of the 12-week Treatment Period
Secondary
To compare the efficacy of relamorelin with 
placebo in participants with DG with respect to the 
following individual symptoms of the DGSSS:

Nausea

Abdominal Pain

Postprandial fullness

Bloating
To compare the safety of relamorelin with placebo 
in participants with DG
Secondary
Individual Symptom (ie, nausea, abdominal pain, 
postprandial fullness, and bloating) Responder, 
defined as a participant with at least a 2-point 
decrease in the change from baseline on the weekly 
average of the symptom severity (at its worst) 
during each of the last 6 weeks of the 12-week 
Treatment Period 
AEs, clinical laboratory values, vital signs, ECGs, 
HbA1c, and anti-relamorelin antibodies
Clinical Hypotheses
The clinical hypotheses are:
1) DG participants receiving relamorelin compared to DG participants receiving placebo will 
experience greater improvement in DGSSS. 
2) A greater proportion of DG participants receiving relamorelin compared to DG participants 
receiving placebo will achieve “Vomiting Responder” status, defined as a participant with zero 
weekly vomiting episodes during each of the last 6 weeks of the 12-week Treatment Period.
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5.
Study Design
5.1.
Overall Design

Global, multicenter, randomized, double-blind, placebo-controlled, parallel-group 

Treatment Groups: Relamorelin 10 μg or placebo, twice daily, SC 

Study Duration: Up to 18 weeks, including a 12-week Treatment Period

Study Periods: Screening Period of up to 4 weeks, a 2-week Run-in Period, and a 12-week 
Treatment Period as follows:
o
Run-in Period: Participants who meet initial study entry criteria during the Screening 
Period will enter a 2-week placebo Run-in Period, during which they will self-
administer single-blind placebo twice daily, SC. Using an electronic hand-held device, 
participants will report their symptoms via the Diabetic Gastroparesis Symptom 
Severity Diary (DGSSD) as well as their 
 
compliance, and use of rescue medication. 
o
12-week Treatment Period: Participants who meet entry criteria at the end of the Run-
in Period, will be randomized 1:1 to blinded treatment with relamorelin 10 µg or 
placebo. Participants will continue to use the electronic hand-held device for reporting 
of their symptoms via the DGSSD as well as their 
 
 compliance, and use of rescue medication.
See Figure 2 for a Study Schematic.
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Figure 2:
RLM-MD-01 Study Schematic
Study Population:

Screening: Males and females aged 18 years and older with T1DM or T2DM with controlled 
and stable blood glucose levels and HbA1c ≤ 11%; symptoms suggestive of DG for at least 3 
months, with mechanical obstruction of the gastrointestinal (GI) tract as the cause of 
symptoms having been ruled out; history of at least 2 vomiting episodes 

During the Run-in Period: At least 1 vomiting episode and delayed GE by gastric emptying 
breath test (GEBT)

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, no treatment with GI promotility agents during the Run-in Period, at least 
1 vomiting episode reported during the 2-week Run-in Period; and a score of ≥ 16 for the 
average of the daily DGSSS assessments measured during the Run-in Period.
Screening
Treatment Period
SB PBO
Run-in Period
12-Wk DB
Treatment Period
Wk -6
Wk -3
Wk -2
Wk -1
Wk 2
Wk 4
Wk 8
Wk 12
EOT
Day -42 to -15
Day -14 to -1
Day 14
Day 28
Day 56
Day 84
V1
V2
V4
V5
V6
V7
Day 1
GEBT
PBO (n=300)
RLM (n=300)
PROs completed at Treatment Period visits
eDiary Completion of DGSSD daily, beginning at Day 1 of SB PBO Run-in Period through end of DB Treatment Period
GEBT=gastric emptying breath test; SB=single-blind; DB= double-blind; PBO=placebo; RLM=relamorelin; Wk=week; V=visit; EOT=end of 
treatment; n=number of patients; PRO=patient reported outcome; DGSSD=Diabetic Gastroparesis Symptom Severity Diary
V3
Randomization
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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.
Assuming they meet entry criteria, participants who successfully complete this study are eligible 
to enter a placebo-controlled, long-term safety and efficacy study (RLM-MD-03) during which 
they will receive study treatment for an additional 46 weeks.
5.2.
Participant and Study Completion
Approximately 2500 participants will be screened at approximately 350 study sites (globally) to
achieve 600 participants randomly assigned to study treatment (300 participants per treatment 
group). A total of 480 participants are expected to complete the study (240 participants per 
treatment group). See Section 10.1 for details on sample size determination.
5.3.
End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study.
A participant is considered to have completed the study if he/she has completed all phases of the 
study including at least 84 days of treatment, and the last 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 30 days after 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.
5.4.
Scientific Rationale for Study Design
The sponsor has designed this randomized, double-blind, placebo-controlled, parallel-group 
study to follow regulatory recommendations 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 inclusion as part of the development plan of a 
long-term placebo-controlled safety study (12 months, with appropriate prespecified provisions 
for rescue medications).
Several design features have been incorporated in the current study in an effort to minimize bias, 
including a placebo run-in and double-blind design. Random assignment of participants avoids 
bias and helps 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 
relamorelin group and the control group. Furthermore, the placebo run-in period with collection 
of data (symptoms in a daily diary) was incorporated into this study to allow study personnel to 
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assess compliance with and tolerability of these procedures prior to randomization, and to obtain 
robust baseline measurements prior to initiating study treatment dosing. The run-in period also 
allows the confirmation of vomiting symptoms in addition to a history of vomiting.
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 relamorelin in 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 the
3 doses of relamorelin and placebo. Based upon the observed dose response of change-from-
baseline symptom scores collected daily over the course of 12 weeks using the DGSSD, the 
30 µg BID, and 100 µg 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 
10 µg once daily study treatment did not demonstrate significant improvement in symptom relief 
compared to placebo after 28 days of dosing in Study RM-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 efficacy and safety data, the relamorelin dose selected for this study is 10 µg BID.
6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
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6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Male and female participants aged 18 years or older at Screening (Visit 1)
4. DG defined as at least a 3-month history prior to Screening (Visit 1) of symptoms on an 
ongoing basis that are suggestive of GP 
 
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10. Able to provide written informed consent (IC) prior to any study procedures and willing 
and able to comply with study procedures
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
3. Participants who are actively experiencing anorexia nervosa, binge-eating, bulimia, or other 
eating disorder at the time of Screening (Visit 1) are excluded regardless of when diagnosis 
was established.
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 
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10. Currently receiving parenteral feeding or presence of a nasogastric or other enteral tube for 
feeding or decompression
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24. Functional dyspepsia diagnosed before the diagnosis of diabetes mellitus
6.3.
Lifestyle Restrictions
There are no specific dietary restrictions in the study. It is expected that participants are 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 of GP may make this difficult.
For timing of meals around the GEBT, refer to the Study Reference Manual.
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6.4.
Screen Failures
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.
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 1).” In this specific 
situation, the patient may be rescreened after at least 1 month and no more than 6 months of 
further effort to achieve improved glycemic control, as indicated by HbA1c being ≤11.0%. 
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.
The sponsor may permit a participant with a positive UDS by immunoassay, at Screening (Visit 
1) to continue in the Screening Period while confirmatory urine drug screen 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 UDS result for drugs prescribed for the participant (ie, barbiturates, 
benzodiazepines, amphetamines, but not opioids 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 these prescribed drugs on an as-needed basis is not allowed.
Some participants who screen fail after completing the Run-in Period in this study may be 
eligible for entry into a parallel study (RLM-MD-04) but will still be considered screen failures 
in this study.
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, placebo, or 
medical device intended to be administered to a study participant according to the study protocol.
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7.1.
Treatments Administered
Participants are to self-administer double-blind study treatment twice daily, SC, with the first 
daily dose being administered within approximately 30 minutes before the morning meal 
 
 and the second daily dose within approximately 30 minutes 
before the evening meal 
. If a participant does not eat
morning or evening meals, study treatment should be administered during typical meal times 
 
. 
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:
Study treatment will be dispensed as pen injectors with pre-filled cartridges of either relamorelin 
or placebo. Study treatment details are provided in Table 7-1.
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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
Manufacturer
Allergan (Assembled Pen)
Allergan (Assembled Pen)
Injection Device
Utilize Multi-dose Pen Injector for 
the administration of the study 
treatment or placebo. 
Utilize Multi-dose Pen Injector for 
the administration of the study 
treatment or placebo. 
7.1.1.
Run-in Medications and Administration
Placebo (single-blind) should be self-administered twice daily
 
SC using the pen-injector.
7.1.2.
Study Supplies
1. The Allergan-manufactured medical devices 
 
 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 
Appendix 7).
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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 12-week Treatment Period, eligible participants will be randomized in a 
1:1 ratio to blinded treatment with relamorelin 10 µg or placebo. Randomization will be stratified 
by geographic region.
Study treatment will be dispensed at the study visits indicated in the Schedule of Activities 
(SoA) (Section 2).
Returned study treatment should not be re-dispensed to the participants.
7.4.
Blinding
The investigator, investigational staff, and participant will be fully blinded to study treatment 
during the 12-week Treatment Period; during the placebo Run-in Period, single-blind treatment 
with placebo is self-administered. All study treatment will be provided in identical pen injectors 
and cartons to maintain blinding of the study.
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7.5.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use 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 labelled storage 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 unused 
study treatment. 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 (Section 8.1.1).
The study centers will keep an accurate drug disposition record that specifies the amount of 
study treatment dispensed to each participant and the date of dispensing.
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 study must be recorded on the electronic case report form (eCRF) along with:

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 of all concomitant medications taken for chronic 
conditions with the exception of diabetes mellitus (see Section 7.7.2) should be held stable 
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during the study. The sponsor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.7.1.
Prohibited Treatments
The classes of drugs prohibited in the study are, with the exception of SGLT-1 or SGLT-2 
inhibitors, those that affect GI motility, either positively or negatively, and therefore could 
confound the assessment of the efficacy of study treatment on the signs and symptoms of DG. 
The SGLT-1 or SGLT-2 inhibitors are prohibited for 3 days prior to the GEBT done at the start 
of the Run-in Period in all participants and in a subset of participants at a subset of sites at Visit 7 
or the Early Termination Visit. Their mechanism of action is through causing increased 
glycosuria, which may affect interpretation of the GEBT results.
Table 7-2 provides a list of drug classes and treatments that are prohibited during the study and 
require washout 
Table 7-2: 
Prohibited Medications and Washout Requirements
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7.7.2.
Permitted Treatments
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 study must be recorded in the eCRF along with:

Indication

Dates of administration including start and end dates

Dosage information including dose and frequency
DG participants enrolled in this study will likely consist mostly of participants receiving 1 or 
more prescription medications for blood-glucose control. Good clinical practice allows for 
frequent adjustment of medication by participants 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 of a specific medication/treatment is in 
question, please contact the sponsor.
The sponsor or designee should be 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 receive 
a 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 visits during 
the Treatment Period. If a participant requires an anti-emetic drug (eg, 5-HT3 receptor 
antagonists, NK1 receptor antagonists, for more than 1 day a week, 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
Assuming they meet entry criteria, participants who successfully complete this study are eligible 
to enter a placebo-controlled, long-term safety and efficacy study (LTSES) (RLM-MD-03) 
during which they will receive study treatment for an additional 46 weeks.
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Participants who prematurely discontinue from the study and participants who do not enter the 
long-term safety and efficacy study (Study RLM-MD-03) should follow up with the investigator 
regarding treatment at the end of the study. 
8.
Discontinuation/Withdrawal Criteria 
Reasons for discontinuation from study treatment and/or the study may include the following:

Adverse event

Completed

Death

Failure to meet randomization criteria

Lack of efficacy

Lost to follow-up

Other

Investigator decision

Pregnancy

Protocol deviation

Screen failure

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 treatment also requires discontinuation from the study (See Appendix 8
for Standard Discontinuation Criteria/Definitions.).
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8.1.
Discontinuation of Study Treatment
Discontinuation of study treatment also requires discontinuation from 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 treatment for 
abnormal liver function should be considered by the investigator when a participant meets 
criteria for Hy’s law (See Section 9.2.7.1 and Appendix 6) or if the investigator believes that 
it is in best interest of the participant. 

ECGs should be carefully analyzed for findings pointing to potentially important cardiac 
events (also see Section 9.2.7.3). If a clinically significant finding is identified (including, but 
not limited to changes from baseline in QT interval corrected using QTcB or QTcF) after 
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 
QTc value of > 500 msec or an increase from baseline of > 60 msec after start of study 
treatment should prompt discontinuation of the participant from 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 9.2.5 Pregnancy and 
Appendix 5 for 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 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. 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.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 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.
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
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws 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.

See the SoA for data to be collected at the time of study discontinuation.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study.

Before a participant is 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 participant continue 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 concerns should 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 SoA, is essential 
and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
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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 approximately 63 mL 
(plus approximately an additional 64 mL only for participants in the PK and hormone subset). 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
9.1.
Efficacy Assessments
All primary and secondary efficacy assessments are derived from the 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 (Appendix 15). 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).
DGSSD entries are to be made daily at the same time every evening on the electronic hand-held 
device beginning the first day of the Run-in Period and continuing throughout the Treatment 
Period. Planned timepoints for all efficacy assessments are provided in the SoA (Section 2).
9.1.1.
Primary Efficacy Assessments
9.1.1.1.
DGSSS Change from Baseline to Week 12 in the Weekly DGSSS
The change from baseline to Week 12 in the weekly DGSSS has been selected as a primary 
endpoint in this study. 
DGSSS is derived as the sum of the daily DGSSD items of nausea, abdominal pain, postprandial 
fullness, and bloating. Weekly DGSSS is derived as the sum of the weekly averages of the 
DGSSD items of nausea, abdominal pain, postprandial fullness, and bloating. The worst possible 
DGSSS for the 4 DG symptoms is 40, and the best possible DGSSS is 0.
Baseline is the average of the 2 weekly DGSSS from the 2-week, placebo Run-in Period.
9.1.1.2.
Vomiting Responder
Vomiting Responder, based on the number of vomiting episodes, has been selected as a primary 
endpoint in this study. 
A Vomiting Responder is defined as a participant with zero weekly vomiting episodes during 
each of the last 6 weeks of the 12-week Treatment Period. Vomiting is defined as throwing up 
the contents of the stomach. This does not include retching or dry heaving (also known as dry 
vomiting) when no stomach contents are thrown up.
Vomiting frequency will be captured during the placebo Run-in Period and the 12-week 
Treatment Period. Participants will be asked to indicate the number of vomiting episodes 
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experienced in the day since the previous entry made, with information provided as to what 
constitutes a “vomiting episode” in order to ensure accurate reporting. 
9.1.2.
Secondary Efficacy Assessment
9.1.2.1.
DGSSS Individual Item Responders
The individual items assessing nausea, abdominal pain, bloating, and postprandial fullness will 
be assessed as secondary endpoints using the following response definition:
Individual symptom response is defined as an improvement of ≥ 2-points in the weekly symptom 
scores for each individual item at each of the last 6 weeks of the 12-week Treatment Period 
Psychometric analyses have shown that 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).
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9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
AEs will be reported by the participant or noted by the investigator. 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or study procedures, or that caused the 
participant to discontinue the study treatment (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and 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 timepoints 
specified in the SoA (Section 2).
Medical occurrences that begin before the start of study treatment but after obtaining IC will be 
recorded on the Medical History/Current Medical Conditions section of the eCRF not the AE 
section.
All SAEs will 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 sponsor within 
24 hours of it being available.
Investigators are not obligated to actively seek AE or 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.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
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9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, AEs, and non-serious AEs of special interest ([AESI] as 
defined in Appendix 4) will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 8.3). 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 sponsor of a 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 sponsor has 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 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics 
Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy 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 sponsor will review and then 
file it along with the investigator’s brochure and 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.

If a pregnancy is reported, the investigator should inform the sponsor within 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 purpose of study medication 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. 
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The definition of a Medical Device Incident can be found in Appendix 7.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes outlined in 
Section 9.2 and Appendix 4 of 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 incident is 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.

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.

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 the sponsor to fulfill the legal responsibility, if 
needed, to notify appropriate regulatory authorities and 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.
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9.2.7.
Adverse Events of Special Interest
9.2.7.1.
Hy’s Law
Study site personnel must report every participant who meets potential Hy’s Law criteria which 
are as follows: 

ALT or 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). 
A laboratory alert for potential Hy’s laws cases will be in place. Investigators and the sponsor 
must be immediately notified when the above criteria have been met. A potential Hy’s law case 
must be faxed to the sponsor’s SAE/Pregnancy fax number on an Abnormal Liver Function 
Reporting Form (GPSE-PVOPS-F-01-28) and SAE form within 24 hours of learning of the 
potential Hy’s law case to the SAE/Pregnancy fax number, even if no AE has occurred
(Appendix 4). The eCRF for potential Hy’s law cases must be completed within 7 calendar days. 
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 events related 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 diabetic gastroparesis typically 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 including
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revascularization (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.
9.2.8.
Medication Errors
Medication error refers to any unintended error in the dosing and/or administration of the study 
treatment as 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 treatment given per 
administration or per day that is above the maximum recommended dose (10 µg BID or 
20 µg /day) according to the reference safety information or protocol for the study treatment or 
comparator as applicable. This also takes into account cumulative effects due to overdose.
Underdose: Unintentional administration of a quantity of the study treatment given per 
administration or per day that is under the minimum recommended dose according to the 
reference safety information or protocol. Since there is no clinical information on the efficacy of 
relamorelin at a dose less than 10 µg BID, a dose of 10 µg once daily should be considered an 
underdose.
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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 MSP immediately.
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 as the duration of the overdose in the 
site’s source documents for the participant.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the MSP based on the clinical evaluation of the participant.
9.4.
Safety Assessments
Planned timepoints for all safety assessments are provided in 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 sites for clinically significant reactions, will 
be conducted as required at other study visits.
Participants should be weighed with no shoes, in light clothing, without any outerwear; height to 
be measured only at Visit 1. The weight taken at Visit 2 is to be used for the GEBT and will not 
be recorded in the eCRF. 
Any abnormality noted during the physical examination performed at Visit 7 or the Early 
Termination Visit that was not present during the physical examination at Visit 1 should be 
reported as an AE if considered by the investigator to be clinically significant.
9.4.2.
Vital Signs

Heart rate (HR), respiratory rate, systolic and diastolic blood pressure (BP), and temperature 
will be assessed; the method for measuring temperature will be per the site’s preference.

BP and HR measurements 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 HR measurements should be preceded by at least 3 minutes of rest for the participant 
in a quiet setting without distractions (eg, television, cell phones).
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
Vital signs are to be taken before blood collection for laboratory tests. 
9.4.3.
Electrocardiograms

Single 12-lead ECG will be obtained as outlined in the SoA (see Section 2) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. Refer to Section 8.1 for QTc withdrawal criteria; also see Section 9.2.7.3 for Major 
Adverse Cardiovascular Events.
9.4.4.
Clinical Safety Laboratory Assessments

See Appendix 2 for the list of clinical laboratory tests to be performed and refer to the SoA 
(Section 2) 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 AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those that 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 30 days after 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/baseline within 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 Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
o
If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the eCRF.
9.4.5.
Hormonal Assessments
In a subset of participants (approximately 100 in total), at a subset of sites, investigation of the 
effects of study treatment on levels of hormones potentially affected by relamorelin will be 
carried out. These hormones are GH, insulin-like growth factor-1 (IGF-1), insulin, glucagon, 
c-peptide, adrenocorticotropic hormone (ACTH), and cortisol. The participants will be those who 
will undergo the PK assessment at selected sites. A single fasting blood specimen will be 
obtained for measurement of the hormones and fasting blood glucose (FBG) at the visits noted in 
the SoA (Section 2). 
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9.4.6.
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. Sponsor may provide each participant with a glucose monitor, test strips, and all supplies 
necessary for testing finger-stick capillary blood glucose. 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). 
Information from SMBG, in addition to that provided by values of HbA1c and FBG, 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 patient to his/her 
health care provider for the same purpose).
9.5.
Pharmacokinetics
Sparse plasma samples of approximately 2 mL per sample will be collected at a subset of sites on 
a subset of participants to estimate concentrations of relamorelin. These sites will be selected by 
the sponsor to ensure the appropriate sample handling requirements can be met. In total, 
approximately 100 participants will be recruited to provide sparse samples.
The dosing of relamorelin and samples collected will occur at the following intervals: 

At Visit 3, administration of the first dose of study treatment will occur at the site, with the 
time and date recorded. PK samples will be collected within 0.5 hours before dose 
administration, between 0.5 hours and 1 hour after dose administration, and between 
1.5 hours and 3.0 hours after dose administration. 

At Visit 4, Visit 5, Visit 6, and Visit 7, participants are to administer the morning dose of 
study treatment at home, and provide the site with the date and time of the dose 
administration. During these visits, a single PK sample will be collected between 0.5 hours 
and 6.0 hours after dose administration, dependent on the timing of the clinic visit. At the 
Early Termination Visit, a single PK sample will be collected irrespective of the time of the 
last dose administration.
In addition, plasma samples of approximately 4 mL will also be collected to assess the formation 
of anti-relamorelin antibodies in all study participants. Samples will be collected at Visit 3/
Baseline, Visit 4, Visit 7, or Early Termination Visit.
9.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
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9.7.
Genetics
Genetics are not evaluated in this study.
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10.
Statistical Considerations
10.1.
Sample Size Determination
The sample size and statistical power for the DGSSSS endpoint was assessed by simulation. 
Data were simulated for the DGSSS over time under the assumption of a multivariate normal 
distribution and based on and based on mean responses in Study RM-131-009 variance -
covariance structure (Table 14.1 of the SAP). A missing completely at random (MCAR) dropout 
rate of 20% by Week 12 was assumed for each treatment.
Vomiting response rates were assumed to be those observed in Study RM-131-009 (26% and 
11% for treatment and placebo respectively). Sample size was assessed using the POWER 
procedure in SAS. 
The sample size of approximately 300 participants per arm will provide more than 90% power to 
reject at least one of the primary null hypotheses using the multiplicity approach described in 
Section 10.3 of the SAP. 
10.2.
Populations for Analyses
The analysis populations will consist of participants as defined in Table 10-1.
Table 10-1:
Analysis Populations
Population
Definition
Screened
All screened participants who signed the ICF
Intent-to-treat (ITT)
All randomized participants
Modified intent-to-treat (mITT)
All randomized participants with ≥ 1 post-baseline assessment of 
DGSSD 
Pharmacokinetic
All randomized participants who agreed to volunteer for sparse 
PK collection, and provided > 2 evaluable samples during the 
double-blind treatment period
Safety
All participants who received ≥ 1 administration of double-blind 
study treatment
10.3.
Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the participant 
populations to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data. This section is a summary of the planned statistical analyses of the primary 
and secondary endpoints.
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10.3.1.
Key Statistical Methodology
The methodologies defined in Table 10-2 apply as specified to individual endpoints defined in 
this protocol. All statistical tests will be 2-sided hypothesis tests performed at the 5% level of 
significance for main effects. All CIs will be 2-sided 95% CIs, unless stated otherwise.
Table 10-2:
Statistical Methodology
Methodology
Description
Categorical counts

Number of participants in individual categories
a.
Participants with ≥ 1 qualifying event counted once per individual category
Categorical
descriptives

Number and percentage of participants in individual categories
a.
Participants with ≥ 1 qualifying event counted once per individual category

N1 if percentage denominator ≠ number of participants in the population (standard 
percentage denominator)
a.
N1 = participants with nonmissing baseline value
Event descriptives

Number and percentage of events in individual categories
a.
Events counted individually for each instance

Percentage denominator = total number of events
Continuous 
descriptives

N1, mean, SD, median, minimum, maximum

N1 = participants with nonmissing value
Change from baseline 
(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
Responder

Categorical descriptives for responders and nonresponders
a.
Nonresponders include:
i.
Participants who do not meet responder criteria
ii.
Participants with no postbaseline values 

Risk differences and Wald CIs vs [placebo/active comparator]

Estimates derived from Cochran-Mantel-Haenszel (CMH) model controlling for 
factors (treatment group, region)
a.
Mantel-Haenszel (MH) odds ratios (ORs) and CIs vs placebo
b.
P-values comparing treatment group vs placebo

N1 = all participants unless otherwise specified
CFB

Continuous descriptives for CFB 

Estimates derived from Mixed-effects model with repeated measures including fixed 
effects for geographic region, treatment, week, treatment-by-week interaction, as well 
as baseline and baseline-by-week interaction values as the covariates 
a.
LS mean and LS mean difference (CIs) between treatment group and placebo
b.
P-values comparing treatment group vs placebo
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10.3.2.
Efficacy Analyses
10.3.2.1.
Primary and Secondary Endpoints
Table 10-3 displays the primary and secondary efficacy endpoints that will be analyzed for the 
mITT population. All other efficacy endpoints and analyses will be defined in the SAP.
Table 10-3:
Primary and Secondary Endpoints
Primary Endpoints
Description
Timing
Methodology
CFB to Week 12 in 
weekly DGSSS
Change from baseline to Week 12 in 
Weekly DGSSS 
Week 12
CFB
Vomiting Responder
Vomiting responder during last 6 weeks of 
treatment 
Last 6-weeks of 
Treatment Period
Responder
Secondary Endpoints 
Nausea Responder
Nausea responder during last 6 weeks of 
treatment
Last 6-weeks of 
Treatment Period
Responder
Abdominal Pain 
Responder
Abdominal Pain responder during last 6 
weeks of treatment
Last 6-weeks of 
Treatment Period
Responder
Bloating Responder
Bloating responder during last 6 weeks of 
treatment
Last 6-weeks of 
Treatment Period
Responder
Postprandial Fullness 
Responder
Postprandial Fullness responder during last 
6 weeks of treatment
Last 6-weeks of 
Treatment Period
Responder
10.3.2.2.
Multiple Comparisons Procedure
To control the overall type-1 error rate of the study, a multiplicity adjustment will be applied to 
the primary and secondary endpoints. For that purpose, the hypotheses of interest will be 
grouped into the 2 families described below: 

Family 1:
o
Hypothesis H1: Comparison of relamorelin vs. placebo in the change from baseline to 
Week 12 in weekly DGSSS 
o
Hypothesis H2: Comparison of relamorelin vs. placebo in Vomiting response rate 

Family 2: 
o
Hypotheses H3-H6: Comparison of relamorelin vs. placebo in the response rates of the 
individual symptoms comprising DGSSS (ie, nausea, abdominal pain, postprandial 
fullness, and bloating)
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The multiple testing will be performed in 2 steps as follows: 
Step 1: Treatment comparisons to placebo in the DGSSS and vomiting response rates will be 
performed using the truncated Holm test at alpha=0.05. A truncation parameter of 0.5 will be 
used. 
Step 2: If any of the comparisons at Step 1 is significant, the treatment comparisons to placebo in 
the individual symptoms response rates will be performed using the regular Holm test at a level 
alpha which depends on the unused alpha from Step 1. 
Details for other efficacy analyses are provided in the SAP. 
10.3.2.3.
Missing Data
Participants with a missing weekly value for the vomiting frequency or the individual symptoms 
comprising the DGSSS (i.e., nausea, abdominal pain, postprandial fullness, and bloating) during 
any of the last 6 weeks will be analyzed as a non-responder for the endpoint. 
Analysis for two primary endpoints based on multiple imputations (MI) as proposed by 
Little and Rubin (1987) will be also be provided. MI for weekly vomiting episodes will be 
performed under both missing at random and missing not at random (MNAR) assumptions and 
MI for change from baseline in the weekly DGSSS will be performed only under MNAR 
assumption. 
Detailed methods and procedures for the above outlined missing data-derived sensitivity 
analyses, planned or exploratory, will be documented in the final SAP prior to the study 
completion.
10.3.3.
Safety Analyses
All safety analyses will be performed 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 hypoglycaemia-related events

Clinical laboratory assessments
o
Potential Hy’s law cases
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
Vital signs

ECGs

Study-specific assessments
o
HbA1c
10.3.5.
Interim Analyses 
In addition to the above, monitoring of patient 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 in the protocol. Study conduct may be 
interrupted or terminated by the Sponsor based on DSMB recommendation if safety data become 
available which appear to represent an undue risk to the study patients’ health or well-being. 
Further details of the DSMB (composition, policy, and procedures) are specified in a separate 
DSMB Charter.
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11.
References
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):852-60.
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 Loge C, Trudeau E, Marquis P, Kahrilas P, Stanghellini V, Talley NJ, Tack J, Revicki DA, 
Rentz AM, Dubois D. 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):1751-62. 
de La Loge C, Trudeau E, Marquis P, Revicki DA, Rentz AM, Stanghellini V, Talley NJ, 
Kahrilas P, Tack J, Dubois D. 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.
Hopkins Medicine, 2013. 
http://www.hopkinsmedicine.org/gastroenterology_hepatology/_pdfs/esophagus_stomach/gastro
paresis.pdf. Accessed 04Nov2015.
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.
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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):1001-15.
Little RJA and Rubin DB (1987) Statistical Analysis with Missing Data. John Wiley & Sons, 
New York.
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 Researc Consortium. Similarities and differences between 
diabetic and idiopathic gastroparesis. Clin Gastroenterol Hepatol. 2011; 9:1056–64.
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.
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. Pharmacoeconomics 1993;4:353-65.
Rentz AM, Kahrilas P, Stanghellini V, Tack J, Talley NJ, de la Loge C, et al. Development and 
psychometric evaluation of the patient assessment of upper gastrointestinal symptom severity 
index (PAGI-SYM) in patients with upper gastrointestinal disorders. Qual Life Res. 2004 
Dec;13(10):1737-49.
Revicki DA, Camilleri M, Kuo B, Norton NJ, Murrary L, Palsgrove A, Parkman HP. 
Development and content validity of a gastroparesis cardinal symptom index daily diary. 
Aliment Pharmacol Ther. 2009;30(6):670-80.
RTI Health Solutions, Psychometric Evaluation of the Diabetic Gastroparesis Symptom Severity 
Diary Using RM-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;24:531–4.
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for 
Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation. July 2009. 
https://www.fda.gov/downloads/Guidances/UCM174090.pdf Accessed 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.
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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.
Ware JE, Kosinski M, Keller S. A 12-Item Short-Form health survey: construction of scales and 
preliminary tests of reliability and validity. Medical Care. 1996;34:220-33.
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12.
Appendices
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12.1.
Appendix 1: Abbreviations
ACTH
adrenocorticotropic hormone
ADA
anti-drug antibodies
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST 
aspartate aminotransferase
BID
twice daily
CBC
complete blood count
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
DFU
directions for use
DG
diabetic gastroparesis
DGSSD
Diabetic Gastroparesis Symptom Severity Diary
DGSSS
Diabetic Gastroparesis Symptom Severity Score
DILI
drug-induced liver injury
ECG
electrocardiogram
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eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ET
early termination
EU
European Union
FBG
fasting blood glucose
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
GH
growth hormone
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
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IEC
Independent Ethics Committee
IGF-1
insulin-like growth factor-1
IND
Investigational New Drug Application
INR
international normalized ratio
IRB
Institutional Review Board
IVCD
intraventricular conduction delay 
IWRS
interactive web response system
MMRM
mixed method for repeated measures
MSP
medical safety physician
NRS
numerical rating scale
PK
pharmacokinetic
PRO
patient-reported outcome
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-1
sodium-glucose co-transporter-1
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SGLT-2
sodium-glucose co-transporter-2
SMBG
self-monitoring of blood glucose
SoA
Schedule of Activities
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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Electronic Signatures
User
Date
Justification

SAP_001.pdf: 
NCT03285308 
 
Study ID: RLM‐MD‐01 
 
 
Title:  A 12‐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 2 Date: 17Nov2020 


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Title Page
RLM-MD-01
A 12-week, Randomized, Double-blind, Placebo-controlled, Phase 3 Study to Evaluate the 
Safety and Efficacy of Relamorelin in Patients with Diabetic Gastroparesis
RLM-MD-02
A 12-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 - Clinical Study Report
Final: 06 December 2018
Amendment 1:  29 September 2020
Amendment 2:  17 November 2020


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Table of Contents
1.0
Title Page ........................................................................................................................................................1
2.0
Table of Contents ............................................................................................................................................2
2.1
List of Tables ....................................................................................................................................3
2.2
List of Figures...................................................................................................................................4
3.0
List of Abbreviations.......................................................................................................................................5
4.0
Introduction.....................................................................................................................................................7
4.1
Study Design.....................................................................................................................................7
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 and Treatment Compliance............................................................................................17
9.1
Extent of Exposure..........................................................................................................................17
9.2
Measurement of Treatment Compliance.........................................................................................17
10.0
Efficacy Analyses..........................................................................................................................................18
10.1
Primary Efficacy Parameters...........................................................................................................18
10.1.1
Primary Analysis ..............................................................................................................19
10.1.2
Sensitivity Analysis for Missing data ...............................................................................19
10.2
Secondary Efficacy Parameters.......................................................................................................21
10.3
Multiple Comparisons Procedure....................................................................................................22
10.5
Subgroup Analyses .........................................................................................................................26
10.6
Rescue Medication..........................................................................................................................27
11.0
Safety Analyses.............................................................................................................................................28
11.1
Adverse Events ...............................................................................................................................28
11.1.1
AEs of Special Interest .....................................................................................................29
11.1.2
Medical Device Incidents (Including Malfunctions) ........................................................29
11.2
Clinical Laboratory Parameters.......................................................................................................30
11.3
Vital Signs.......................................................................................................................................32
11.4
Electrocardiogram...........................................................................................................................33
11.5
Study Specific Assessments............................................................................................................34


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11.6
Other Safety Parameters..................................................................................................................34
11.6.1
Physical Examination .......................................................................................................34
11.6.2
Potential Hy’s Law ...........................................................................................................34
11.7
Subgroup Analyses .........................................................................................................................34
13.0
Interim Analysis ............................................................................................................................................37
14.0
Determination of Sample Size.......................................................................................................................38
15.0
Statistical Software........................................................................................................................................39
16.0
Data Handling Conventions ..........................................................................................................................40
16.1
Visit Time Windows .......................................................................................................................40
16.2
Analysis Weeks and Visit Time Windows for Efficacy Analysis...................................................40
16.2.1
Analysis Weeks for Efficacy Analysis .............................................................................40
16.2.2
Visit Windows for Efficacy Analysis ...............................................................................41
16.4
Repeated or Unscheduled Assessments of Safety Parameters ........................................................43
16.5
Missing Date of the Last Dose of Study Treatment ........................................................................43
16.6
Missing Severity Assessment for Adverse Events..........................................................................43
16.7
Missing Causal Relationship to Study Treatment for Adverse Events ...........................................44
16.8
Missing Date Information for Adverse Events................................................................................44
16.9
Missing Date Information for Prior or Concomitant Medications ..................................................45
16.9.1
Incomplete Start Date .......................................................................................................45
16.9.2
Incomplete Stop Date .......................................................................................................46
16.10
Character Values of Clinical Laboratory Parameters......................................................................47
16.11
Definition of Regions and Pooling..................................................................................................47
17.0
Changes to Analyses Specified in Protocol...................................................................................................48
18.0
References.....................................................................................................................................................49
2.1
List of Tables
Table 4.1–1.
Schedule of Activities: Study RLM-MD-01/RLM-MD-02 .......................................................9
Table 11.1.1–1.
AEs of Special Interest.............................................................................................................29
Table 11.2–1.
Criteria for Potentially Clinically Significant Laboratory Tests ..............................................31
Table 11.3–1.
Criteria for Potentially Clinically Significant Vital Signs........................................................33
Table 11.4–1.
Criteria for Potentially Clinically Significant Electrocardiographic Values............................34
Table 16.1–1.
Visit Time Windows for Safety Analysis ................................................................................40
Table 16.2.1–1.
Analysis Time Windows for Efficacy Analysis.......................................................................41


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Table 16.10–1.
Examples for Coding of Special Character Values for Clinical Laboratory Parameters .........47
2.2
List of Figures
Figure 4.1–1.
RLM-MD-01 / RLM-MD-02 Study Schematic .........................................................................8


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3.0
List of Abbreviations 
aCSR
abbreviated clinical study report
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
CFB
change from baseline
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
DG
diabetic gastroparesis
DGSSD
Diabetic Gastroparesis Symptom Severity Diary
DGSSS
Diabetic Gastroparesis Symptom Severity Score
DGSSS-SR
DGSSS Study Responder
GEBT
gastric emptying breath test
eCRF
electronic case report form
ECG
electrocardiogram, electrocardiographic
eDiary
electronic diary
EOT
end of trial
ITT
intent to treat
IP
investigational product
LSMs 
Least squares means
MAR
missing at random
MCMC
Monte-Carlo Markov chain
MI
multiple imputation
mITT
modified intent to treat
MMRM
mixed-effects model with repeated measures
MNAR
missing not at random
OC
observed cases
OR
odds ratio
PCS
potentially clinically significant
QTc
QT interval corrected for heart rate


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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
SAP
statistical analysis plan
SE
standard error
SI
Le Système International d’Unités (International System of Units)
SOC
system organ class
TBL
total bilirubin
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
TFLs
Tables/Figures/Listings 
V-SR
vomiting study responder


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4.0
Introduction
This statistical analysis plan (SAP) provides a more technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data that will be performed for Study RLM-MD-01 
and separately for study RLM-MD-02 as outlined and/or specified in their respective protocols:

RLM-MD-01: Final protocol (version dated 13 Jul 2017) and the most recent amendment 
(Amendment 4 dated 08 Feb 2019).

RLM-MD-02: Final protocol (version dated 3 Oct 2017) and the most recent amendment 
(Amendment 3 dated 05 March 2019).
Specifications of tables, figures, and data listings for each study are contained in a separate 
document.
 
The study was early/prematurely terminated on 04 September 2020 when the letter explaining 
termination activities was sent to all investigators. As a result, the original planned full analyses 
for the study are no longer applicable for the terminated study. Only abbreviated clinical study 
report (aCSR) for RLM-MD-01 and RLM-MD-02 will be developed. 
The statistical analysis plan (SAP) amendment 2 is based on the amendment #1 SAP dated 29 
Sep 2020. The major change to the amendment #1 SAP is to add descriptive analyses for the 
primary and secondary 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.  Please refer to Section 19.2 Appendix 2 for details of the outlined 
analyses for the aCSR.
4.1
Study Design 
Studies RLM-MD-01 and RLM-MD-02 are identical, designed as global, multicenter, 
randomized, double-blind, placebo-controlled, parallel-group in participants with diabetic 
gastroparesis.
In each study, approximately 600 eligible participants will be randomly assigned in a ratio of 1:1 
to 1 of 2 treatment groups as follows:

Treatment Group 1: Relamorelin (RLM) 10 μg BID (n=300)

Treatment Group 2: Placebo BID (n=300)
The duration of each study is 18 weeks, including a 4-week Screening Period, a 2-week single 
blind Run-in Period, and a 12-week Treatment Period: 


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○
Run-in Period: Participants who meet initial study entry criteria during the Screening 
Period will enter a 2-week Run-in Period, during which they will self-administer 
single-blind placebo twice daily subcutaneously. Using an electronic hand-held 
device, participants will report their daily symptoms via the Diabetic Gastroparesis 
Symptom Severity Diary (DGSSD) as well as their overall global impression of 
status, treatment satisfaction, treatment compliance, and use of rescue medication.
○
12-week Treatment Period: Participants who meet study entry criteria at the end of 
the Run-in Period, will be randomized 1:1 to blinded treatment with relamorelin 
10 µg or placebo, and will continue to use the electronic hand-held device for 
reporting of their symptoms via the DGSSD as well as their overall global impression 
of status and change, treatment satisfaction, compliance, and use of rescue 
medication.
Study schematic and schedule of evaluations for Study RLM-MD-01 and Study RLM-MD-02 
are presented in Figure 4.1–1 and Table 4.1–1 respectively. 
Figure 4.1–1.
RLM-MD-01 / RLM-MD-02 Study Schematic
Participants not meeting certain study entry criteria during Screening Period may be eligible to
enter another RLM study (Study RLM-MD-04)
Screening
Treatment Period
SB PBO
Run-in Period
12-Wk DB
Treatment Period
Wk -6
Wk -3
Wk -2
Wk -1
Wk 2
Wk 4
Wk 8
Wk 12
EOT
Day -42 to -15
Day -14 to -1
Day 14
Day 28
Day 56
Day 84
V1
V2
V4
V5
V6
V7
Day 1
GEBT
PBO (n=300)
RLM (n=300)
PROs completed at Treatment Period visits
eDiary Completion of DGSSD daily, beginning at Day 1 of SB PBO Run-in Period through end of DB Treatment Period
GEBT=gastric emptying breath test; SB=single-blind; DB= double-blind; PBO=placebo; RLM=relamorelin; Wk=week; V=visit; EOT=end of 
treatment; n=number of patients; PRO=patient reported outcome; DGSSD=Diabetic Gastroparesis Symptom Severity Diary
V3
Randomization


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5.0
Objectives
For each study, the primary objectives are:

To compare the efficacy of relamorelin with placebo in participants with DG with respect 
to a composite of the following core signs and symptoms of DG:
○
Nausea
○
Abdominal Pain
○
Bloating
○
Postprandial fullness

To compare the efficacy of relamorelin with placebo in participants with DG with respect 
to vomiting frequency
For each study, the secondary objectives are:

To compare the efficacy of relamorelin with placebo in participants with DG with respect 
to the following individual symptoms of the DGSSS:
○
Nausea
○
Abdominal Pain
○
Bloating
○
Postprandial fullness

To compare the safety of relamorelin with placebo in participants with DG


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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 (i.e. participants 
in the Screened Population who are randomized to a treatment group in the study).
6.3
Modified Intent-to-Treat Population
The Modified Intent-to-Treat (mITT) Population will consist of all randomized participants who 
had at least 1 post-baseline assessment of the DGSSD.
The mITT population will be used for all efficacy analyses. In efficacy analyses, participants will 
be included in the treatment group based on the treatment they were randomized to (i.e. 
regardless of the treatment they actually received). 
6.4
Safety Population
The Safety Population will consist of all participants who received at least 1 dose of double-blind 
study treatment.
The Safety population will be used for all safety analyses. In safety summaries, participants will 
be included in the treatment group based on the treatment they actually received regardless of the 
treatment they were randomized to. 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 in each of the 3 study populations (Safety and ITT 
and mITT) will be summarized by treatment group and study center; the number of participants 
screened will be summarized overall only by study center.
Screen-failure participants (ie, participant who consent to participate in the clinical study but not 
randomized) and the associated reasons for failure to randomize will be tabulated for the 
screening period, the run-in period and overall for the Screened Population. The number and 
percentage of participants rolled over to study RLM-MD-04 will be also be tabulated for all the 
participants in the Screened Population who were screen-failed during the run-in period.
The number and percentage of participants who complete the double-blind treatment period and 
of participants who prematurely discontinue during the same period will be presented for each 
treatment group and pooled across treatment groups for the ITT Population. The reasons for 
premature discontinuation from the double-blind treatment period as recorded on the termination 
pages of the electronic case report forms will be summarized (number and percentage) by 
treatment group for the ITT Population. All participants who prematurely discontinue during the
double-blind period will be listed by discontinuation reason for the ITT Population.


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8.0
Demographics and Other Baseline Characteristics
Demographic parameters (eg, age, race, ethnicity, sex) and other baseline characteristics (weight, 
BMI) will be summarized in total and by treatment group for the Safety and ITT Populations.
Abnormalities in participants’ medical and surgical histories will be coded using the Medical 
Dictionary for Regulatory Activities, version 21.1 or newer. The number and percentage of 
participants with abnormalities in medical and surgical histories in each system organ class and 
preferred term will be summarized by treatment group for the Safety Population. Diabetic 
gastroparesis and diabetes mellitus history and history of diabetes gastroparesis symptoms will 
also be summarized by treatment group for the Safety Population.
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. Any prior medications started more than 
30 days before the date of the first dose of double-blind study treatment and any concomitant 
medications started after the date of the last dose of double-blind study treatment will not be 
presented in the summary tables, but will be included in the participant data listings.
Both prior and concomitant medication use will be summarized by the number and proportion of 
participants in each treatment group for the Safety Population. 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 category and drug preferred name. Multiple 
medications used by a participant will only be counted once for the coded drug preferred name or 
therapeutic class.


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9.0
Extent of Exposure and Treatment Compliance
9.1
Extent of Exposure
Exposure to the study treatment for the Safety Population during the double-blind treatment 
period will be summarized for treatment duration, calculated from the eDiary as the number of 
days from the date of the first dose of study treatment to the date of the last dose of study 
treatment, inclusive. Descriptive statistics (number of participants, mean, SD, median, Q1, Q3, 
minimum, and maximum) will be presented by treatment group. The date of first dose is the date 
of randomization(date of baseline visit).
Patient-years, defined as duration of exposure to the study treatment in years, will be 
summarized by treatment for the Safety Population.
9.2
Measurement of Treatment Compliance
Dosing compliance for a specified period is defined as the number of injections actually taken by 
a participant during that period divided by the number of injections expected for the same period 
multiplied by 100. The number of injections actually taken is obtained from the participants’ 
responses in the item of ‘How many injections of study medication have you administered 
today?’ from the electronic hand-held device. The number of injections expected during a period 
is the number of days in the period multiplied by 2.
Descriptive statistics for study drug compliance will be presented by treatment group for each 
treatment week, for the last 6-week treatment period (i.e., Week 7-12) and for the whole 
double-blind treatment period (ie, Week 1-12), based on the Safety Population. Weeks are 
defined relative to randomization day as described in Section 16.0. 


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10.0
Efficacy Analyses
The efficacy analyses will be based on the mITT Population.  
Most efficacy parameters will be derived from the 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 (Appendix 1). For purposes of the analyses, weekly values will be calculated from the 
daily e-diary data as described in Section 16.3 of this SAP. For weeks with less than 4 days of 
available DGSSD data, weekly values will be set to missing.
Baseline values for parameters are derived from the DGSSD collected in the Run-in period,
(ie, Diabetic Gastroparesis Symptom Severity Score (DGSSS: sum of nausea, abdominal pain, 
postprandial fullness, and bloating), nausea, abdominal pain, postprandial fullness, bloating, 
early satiety, vomiting frequency and vomiting severity) following the steps below: 

Weekly value for Week -2 and Week -1 will be the average value of DGSSD in the week 
(See the analysis week definition for Week -2 and Week -1 in Section 16.2.1); 

Baseline will be the average of the two weekly values of Week -2 and Week -1.
All statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance for 
main effects. All confidence intervals will be 2-sided 95% confidence interval, unless stated 
otherwise.
10.1
Primary Efficacy Parameters
There are two primary efficacy parameters in each study as follows:
a) Change from Baseline to Week 12 in the weekly DGSSS: Baseline is the average of 
the 2 weekly DGSSS from the 2-week, placebo Run-in Period.  
b) Vomiting Study Responder (V-SR): A Vomiting Study Responder is defined as a 
participant with zero weekly vomiting episodes during each of the last 6 weeks of the 
12-week Treatment Period. 
In this study, the primary efficacy analysis (see Section 10.1.1 below) is said to have achieved 
the primary study objective if it indicates that relamorelin is superior to placebo for testing on at 
least one of the two primary efficacy parameters (following the specified multiplicity testing 
procedure as described in Section 10.3).  


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10.1.1
Primary Analysis
10.1.1.1
Change from Baseline to Week 12 in the Weekly DGSSS
The primary efficacy parameter, the change from baseline to Week 12 in the weekly DGSSS, 
will be analyzed using a longitudinal, mixed-effects model with repeated measures (MMRM) 
approach. 
The MMRM model will include fixed effects for geographic region, treatment, week, treatment-
by-week interaction, as well as baseline and baseline-by-week interaction values as the 
covariates with unstructured variance-covariance matrix being common to all participants for the 
repeated measures over weeks. In case the model will not converge with the unstructured 
covariance structure, the Toeplitz structure (TOEP) will be used instead. Least square (LS) mean 
changes from baseline for each treatment group, and LS mean difference between RLM group 
and placebo group, and the associated 95% confidence interval for the difference will be 
provided, along with the reported p-values (two-sided). 
In addition, cumulative distribution function plot will be presented for the change from baseline 
to Week 12 in the Weekly DGSSS for each treatment group. 
10.1.1.2
Vomiting Study Responder (V-SR)
For the primary efficacy responder parameter V-SR, the proportion of responders in the RLM 
group and the placebo group will be analyzed by the Cochran-Mantel-Haenszel (CMH) test 
controlling for geographic region. The number, percentage, and the 95% confidence interval for 
the percentage of Responders by treatment group, the difference in responder rates between the 
RLM and the placebo group and its corresponding 95% confidence interval, and the 2-sided 
p-value associated with the above CMH test will be presented. The Mantel-Haenszel estimate of 
odds ratio (RLM divided by Placebo) - controlling for geographic region- and the corresponding 
95% confidence interval will also be provided.
A participant will be considered a vomiting study non-Responder (ie not a V-SR) if the weekly 
number of vomiting episodes is missing for any of the last 6 weeks of the 12-week Treatment 
Period.
10.1.2
Sensitivity Analysis for Missing data
Missing weekly DGSSS and missing number of weekly vomiting episodes will be imputed using 
multiple imputation (MI) approaches. MI will be performed under Missing at Random (MAR) 
and Missing not at random (MNAR) assumptions using the SAS/STAT procedures PROC MI 
and PROC MIANALYZE. 
10.1.2.1
Sensitivity Analysis for Missing Data of Vomiting Study Responder
MI for V-SR will be performed under both MAR and MNAR assumptions. We will follow the 
steps below to generate datasets and analyze the data: 


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1. Imputed datasets generation
a) Missing at Random (MAR): The imputation of post baseline weekly values will 
be based on a multivariate normal distribution. In each imputation, a Monte-Carlo 
Markov chain (MCMC) method will be used to impute the missing values of post 
baseline weekly values from the observed data of the same group. The initial 
mean vector and covariance matrix for the MCMC will be obtained using an 
expectation–maximization algorithm. 
b) Missing not at random (MNAR): The implementation of the pattern-mixture 
model with control-based pattern imputation of Ratitch and O’Kelly (2011) will 
be used to impute missing data under the MNAR assumption.
o
Intermittent (non-monotone) missing data in both treatment groups are 
imputed using the MCMC method under the MAR assumption as 
described in Step 1- a. 
o
remaining monotone missing data are imputed using a pattern-mixture 
model approach using a sequential regression imputation model estimated 
based on data from the placebo arm only.
Imputed values for the number of weekly vomiting episodes will be restricted to ≥ 0 post 
imputation. 50 imputed datasets will be generated. 
2. Calculate V-SR rate in the imputed datasets.  
3. Model-based key estimates (odds ratio and standard error) will be obtained for V-SR for
each imputed dataset using the same method as described in Section 10.1.1.2.
4. Take the log transformation for odds ratio (log(OR)) and calculate standard error of 
transformed estimate (SE(log(OR))) in each imputed dataset. SE(log(OR)) is obtained
from the log-transformed lower and upper confidence limits for the odds ratio estimate.
5. Output the combined log(OR), SE(log(OR)), and p-values for all imputed datasets using 
PROC MIANALYZE.
6. Back transform the combined results of OR and SE and calculate 95% CI, by taking the 
exponentiation of the point estimates for log(OR) and for the lower and upper CI limits 
for log(OR) (Ratittch et al. ,2013).


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10.1.2.2
Sensitivity Analysis for Missing Data of Change from Baseline in the 
Weekly DGSSS
MMRM analysis of change from baseline in the weekly DGSSS is based on the assumption of 
MAR and this approach uses available data including data from participants with partial data to 
estimate the mean treatment effect without filling in the missing data (Mallinchrod et al., 2008). 
Thus, MI for change from baseline in the weekly DGSSS will be performed only under MNAR 
assumption.  The following steps will be followed to generate datasets and analyze the data: 
1. Imputed datasets generation: Use the method as described in Step 1 Part b) in 
Section 10.1.2.1 to generate 50 datasets. Imputed values for change from baseline in the 
weekly DGSSS will be restricted to ≥ -40 and <=40.
2. Model based key estimates (LSMean difference between treatment group and standard 
error) will be obtained for the change from baseline to week 12 in the weekly DGSSS for
each imputed dataset using the same method as described in Section 10.1.1.1.
3. Calculation of the combined mean difference, 95% CI, and p-value for the change from 
baseline to week 12 in the weekly DGSSS will be done using the method proposed by 
Rubin (1987) via PROC MIANALYZE. 
10.2
Secondary Efficacy Parameters
There are four secondary efficacy parameters, which are all defined for the last 6 weeks of the 
12-week Treatment Period, as follows:

Nausea responder: a study participant is considered a nausea responder for the study if 
he/she has an improvement of ≥ 2-points in the weekly nausea symptom score for each of 
the last 6 weeks during the 12-week Treatment Period.

Abdominal pain responder: a study participant is considered an abdominal pain 
responder for the study if he/she has an improvement of ≥ 2-points in the weekly 
abdominal pain symptom score for each of the last 6 weeks during the 12-week 
Treatment Period.

Bloating responder: a study participant is considered a bloating responder for the study 
if he/she has an improvement of ≥ 2-points in the weekly bloating symptom score for 
each of the last 6 weeks during the 12-week Treatment Period.

Postprandial fullness responder: a study participant is considered a postprandial 
fullness responder for the study if he/she has improvement of ≥ 2-points in the weekly 
postprandial fullness symptom score for each of the last 6 weeks during the 12-week 
Treatment Period.


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If a participant does not have individual item data for a particular symptom during any of the last 
6 weeks of the 12-week Treatment Period, then the participant will not be considered a study 
responder for that symptom.
The proportion of responders in the RLM treatment group and placebo group for each secondary 
efficacy parameter will be analyzed using the analysis method as described for the V-RS primary 
parameter (Section 10.1.1.2).
10.3
Multiple Comparisons Procedure
The overall study Type 1 error will be controlled for the 6 efficacy parameters, 2 primary and 4 
secondary parameters, as defined above (Sections 10.1 and 10.2).  To control the overall type-1 
error rate of the study, the hypotheses of interest will be grouped into the following two families: 

Family 1:
○
Hypothesis H1: Comparison of relamorelin vs. placebo in change from baseline to 
Week 12 in the Weekly DGSSS
○
Hypothesis H2: Comparison of relamorelin vs. placebo in proportion of participants 
who achieved responder status for V-SR

Family 2: 
○
Hypotheses H3-H6: Comparison of relamorelin vs. placebo in the response rates of 
the individual symptoms comprising DGSSS (ie, nausea, abdominal pain, bloating 
and postprandial fullness)
Then, multiple testing will be performed in two steps (Dmitrienko et. al., 2008) as follows: 

Step 1: Treatment comparisons to placebo in change from baseline to Week 12 in the 
Weekly DGSSS and vomiting response rates will be performed using the truncated Holm 
test at alpha=0.05. A truncation parameter of 0.5 will be used. According to this 
procedure, the smallest and largest p-values will be compared to the critical values of 
0.025 and 0.0375 respectively in a step-down manner (i.e. starting with the smallest p-
value and stopping the testing with the first non-rejected hypothesis). 

Step 2: If any of the comparisons at Step 1 is significant, the treatment comparisons to 
placebo in the individual symptoms response rates will be performed using the regular 
Holm test at a level alpha that depends on the unused alpha from Step 1 as follows: 
1) If both H1 and H2 are both rejected in Step 1, H3-H6 will be tested using an 
overall alpha=0.05
2) If only one of H1 and H2 is rejected in Step 1, H3-H6 will be tested using an 
overall alpha=0.0125
3) If none of H1 and H2 is rejected, the testing procedure will be stopped and H3-H6 
are not tested 


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According to the above procedure, the k-th ordered p-value in 1) and 2) in Step 2 will be 
compared to the critical values of alpha/(4-k+1), k=1, , 4, in a step-down manner (i.e. starting 
with the smallest p-value and stopping the testing with the first non-rejected hypothesis), where 
alpha is the significance level from Step 2. 


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10.5
Subgroup Analyses
The analyses of the primary parameters will be presented by selected subgroups as below: 

Diabetes type (Type I / Type II)

Baseline HbA1c (<9% vs >=9%)

Gender 
These subgroup analyses will be contingent on the presence of an adequate number of 
participants in each subgroup. Only descriptive summary in the study level will be provided.
Statistical comparisons within subgroups based on the pooled data will be performed separately
in the integrated efficacy analysis.  


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For the analyses of diabetes subgroups, participants will be classified as having Type I Diabetes 
Mellitus if “Type 1 Diabetes Mellitus” is selected as their answer on the Diabetic Gastroparesis 
and Diabetes Mellitus History eCRF page and/or if the results of T1DM antibody tests at the 
baseline visit (V3) include at least one positive result for the 3 T1DM antibodies being tested 
(Anti-GAD Antibody ≥ 5.00 U/mL = positive, IA2 Autoantibody ≥ 7.50 U/mL = positive, Zn-T8 
Antibody ≥ 15 U/mL = positive). Participants with history of Type 2 Diabetes Mellitus and no 
positive result on any the 3 different T1DM antibodies will be classified as Type II Diabetes 
Mellitus.
10.6
Rescue Medication 
The proportion of participants who took any rescue medication (RM) will be presented by week 
and treatment, and by treatment for the entire duration of the 12-week double-blind treatment 
period. Rescue medication use will also be summarized as percent of days with RM use, 
calculated for each participant as the number of days with RM over the number of days in the 
entire double-blind treatment period. 
To assess the impact of rescue medication use on the assessment of effectiveness, the analyses 
for the primary parameters will be repeated but with the weekly DGSSS and vomiting frequency 
values considered missing following use of RM for two days or more during a week. As a result, 
participants with two or more than two days of RM use during a week for one or more weeks 
during the last 6 weeks of treatment will not be considered as Vomiting Study Responders.


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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, and vital sign parameters. 
For each safety parameter of the clinical laboratory, electrocardiogram, and vital sign 
parameters, the last nonmissing safety assessment before the first dose of double-blind 
investigational product will be used as the baseline for all analyses of that safety parameter. 
Continuous variables will be summarized by number of participants and mean, SD, median, Q1, 
Q3, minimum, and maximum values. Categorical variables will be summarized by number and 
percentage of participants.
11.1
Adverse Events
Adverse events will be coded by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 21.1 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 meets 
SAE criteria. The number and percent of participants with TEAEs, TEAEs leading to 
discontinuation, Deaths, and TESAEs will be presented by treatment.
The number and percentage of participants reporting TEAEs in each treatment group will be 
tabulated by descending percentage in the RLM group, by system organ class (SOC) and 
preferred term and by system organ class, preferred term, and severity.
The number and percentage of participants reporting treatment related TEAEs will be tabulated 
by system organ class and preferred term.
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 in the Safety Population who have TEAEs leading to 
premature discontinuation of the study treatment will be summarized by SOC/ preferred term 
and treatment.
The incidence of common (≥ 2% of participants in any treatment group) TEAEs will be 
summarized by system organ class, preferred term, and treatment group.


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The number and percentage of participants who have TESAE will be summarized by 
SOC/preferred term and treatment group. 
In addition, separate tabular displays for participants who died, participants with SAEs, 
participants with TEAEs leading to premature discontinuation will be presented.
11.1.1
AEs of Special Interest
Hyperglycemia- and hypoglycemia-related events and potential Major Adverse Cardiovascular 
Events (MACE) listed on the Table 11.1.1–1 below are considered AEs of special interest 
(AESI).
Table 11.1.1–1.
AEs of Special Interest
Category
Adverse Event or Preferred term
Hyperglycemia
Blood glucose increased
Diabetes mellitus inadequate 
control
Diabetes with hyperosmolarity
Diabetic coma
Diabetic hyperglycaemic coma
Diabetic hyperosmolar coma
Diabetic ketoacidosis
Diabetic ketoacidotic 
hyperglycaemic coma
Hyperglycaemia
Hyperglycaemic seizure
Hyperglycaemic unconsciousness
Hyperosmolar hyperglycaemic 
state
Ketoacidosis
Hypoglycemia
Blood glucose decreased
Hypoglycaemia
Hypoglycaemia unawareness
Hypoglycaemic coma
Hypoglycaemic encephalopathy
Hypoglycaemic seizure
Hypoglycaemic unconsciousness
Shock hypoglycaemic
MACE
Death from cardiovascular causes 
Non-fatal myocardial infarction
Non-fatal stroke 
An AE will be considered a treatment-emergent AESI (TEAESI) if it is a TEAE that also is an 
AESI. The number and percentage of participants in the Safety Population who have TEAESI 
will be summarized by AESI Category, Adverse Event/Preferred Term and treatment group.
11.1.2
Medical Device Incidents (Including Malfunctions)
The number and percentage of participants in the Safety Population who have AEs related to 
study device (ie., pen injector) will be summarized by preferred term and treatment. In addition, 
the number and percentage of participants in the Safety Population with device malfunctions will 
be summarized by treatment.
Medical device incidents and device malfunctions during run-in period will be only presented in 
the Listing.


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11.2
Clinical Laboratory Parameters
Descriptive statistics for clinical laboratory values (in SI units) and changes from the baseline 
values at each assessment time point will be presented by treatment group for the following 
laboratory parameters:
Hematology
Platelet count RBC count
Hemoglobin
Hematocrit
% Reticulocytes
WBC count
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Clinical 
BUN
Creatinine
Fasting blood glucose Hemoglobin A1c 
Chemistry
Potassium
Chloride
Bicarbonate
Sodium 
Calcium
Phosphorus 
Uric acid
Aspartate 
aminotransferase
Alanine aminotransferase
Alkaline 
phosphatase
Total bilirubin
Direct bilirubin
Total protein
Albumin
cholesterol
triglycerides HDL 
cholesterol
LDL cholesterol
Other Laboratory
C-peptide
Assessments
Urinalysis
pH
Specific gravity
Clinical laboratory test values 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 postbaseline 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 postbaseline 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 postbaseline 
value for the double-blind Treatment Period. A supportive tabular display of participants with 
PCS postbaseline values will be provided, including the PID number, trial center number, and 
baseline and all postbaseline (including non-PCS) values.
In addition, tabular displays showing all AEs that occurred in participants who had 
PCS postbaseline clinical laboratory values will be provided.
Shift tables from baseline to end of trial (EOT) for clinical laboratory parameters will be 
presented by treatment group for the following categories: low, normal, and high.


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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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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
Descriptive statistics for vital signs (oral temperature, respiratory rate, systolic and diastolic 
blood pressure, pulse rate, and body weight) and changes from baseline values at each visit and 
at EOT will be presented by treatment group.
Vital sign values will be considered PCS if they meet both the observed-value criteria and the 
change from baseline criteria listed in Table 11.3–1. The number and percentage of participants 
with PCS postbaseline 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 (for respiratory rate & temperature) or baseline values (for other 
parameters) and at least 1 postbaseline assessment for the double-blind Treatment Period. The 
numerator will be the total number of participants with available baseline values and at least 1 
PCS postbaseline value for the double-blind Treatment Period. A supportive tabular display of 
participants with PCS postbaseline values will be provided, including the PID number, trial
center number, and baseline and all postbaseline (including non-PCS) values.
In addition, a tabular display showing all AEs that occurred in participants who had PCS 
postbaseline vital signs values will be provided.


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Table 11.3–1.
Criteria for Potentially Clinically Significant Vital Signs
Parameter
Flag
Criteriaa
Observed Value
Change From Baseline
Sitting systolic blood 
pressure, mm Hg
High
≥ 180
Increase of ≥ 20
Low
≤ 90
Decrease of ≥ 20
Sitting diastolic blood 
pressure, mm Hg
High
≥ 105
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Sitting pulse rate, bpm
High
≥ 120
Increase of ≥ 15
Low
≤ 50
Decrease of ≥ 15
Weight, kg
High
—
Increase of ≥ 7%
Low
—
Decrease of ≥7%
Respiratory Rate, bpm
High
≥ 24
—
Low
≤ 8
—
Temperature, °C
High
≥ 38
—
Low
≤ 35
—
a
A postbaseline value is considered potentially clinically significant if it meets both the observed-value and the change from
baseline criteria.
bpm = beats per minute.
11.4
Electrocardiogram
Descriptive statistics for ECG parameters (heart rate, RR interval, PR interval, QRS interval, QT 
interval, and QTc) and changes from baseline values at each assessment time point to the end of 
study will be presented by treatment group. The QTc will be calculated using both the Bazett and 
Fridericia corrections.
Electrocardiographic parameter values are considered PCS if they meet or exceed the 
higher-limit PCS criteria listed in Table 11.4–1. The number and percentage of participants with 
PCS postbaseline ECG 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 postbaseline assessment for the double-blind 
treatment period. The numerator is the total number of participants with available non-PCS 
baseline values and at least 1 PCS postbaseline value for the double-blind treatment period. A 
supportive tabular display of participants with PCS postbaseline values will be provided, 
including the PID number, baseline, all postbaseline (including non-PCS) values, and change 
from baseline.
In addition, a tabular display showing all AEs that occurred in participants who had postbaseline 
PCS ECG values will be provided.


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Table 11.4–1.
Criteria for Potentially Clinically Significant Electrocardiographic Values
Parameter
Unit
Criterion Value a
Change from Baseline a
QRS duration
msec
≥ 150
—
PR interval
msec
≥ 250
—
QTc (QTcB, QTcF) interval
msec
> 500
Increase of > 60
a post-baseline (end-of-study or post-dose) value will be considered potentially clinically significant if it meets the criterion 
value or the change from baseline or pre-dose value.
PCS = potentially clinically significant; QTc = corrected QT interval; QTcB = QT interval/RR1/2;
QTcF = QT interval/RR1/3.
11.5
Study Specific Assessments
Study-specific assessments (HbA1c, IGF-1 etc.) are summarized as part of the overall clinical 
laboratory assessments.
11.6
Other Safety Parameters
11.6.1
Physical Examination 
Any new physical examination abnormality identified on the postbaseline physical examination 
or any physical examination abnormality noted as worsened from Screening (Visit 1) to the 
postbaseline physical examination will be reported as an AE if considered by the investigator to 
be clinically significant. No separate data analysis for physical exams is planned.
11.6.2
Potential Hy’s Law
Potential Hy’s Law criteria within a 24 hour window is defined by a post baseline elevation of 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3x ULN, along with total 
bilirubin (TBL) ≥ 2x ULN and a non-elevated alkaline phosphatase (ALP) < 2x ULN, all based 
on blood draws collected within a 24 hour period. 
Potential Hy’s Law criteria without time window (e-DISH) is defined by maximum of post 
baseline elevation of ALT or AST ≥ 3x ULN, along with maximum of post baseline elevation of 
TBL ≥ 2x ULN and a non-elevated alkaline phosphatase (ALP) < 2x ULN. 
Participants who meet the potential Hy’s Law criteria from the first dose of study drug to within 
30 days after the last dose of study treatment will be summarized. Supportive tabular displays 
will also be provided.
11.7
Subgroup Analyses
Selected TEAE summaries (TEAEs by SOC/PT and treatment related TEAEs by SOC/PT) will 
be presented by selected subgroups as below: 


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
Diabetes type (Type I / Type II)  

Baseline HbA1c (<9% vs >=9%)

Gender 


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13.0
Interim Analysis
No interim analysis is planned for this study.


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14.0
Determination of Sample Size
The sample size and statistical power for the DGSSSS endpoint was assessed by simulation. 
Data were simulated for the DGSSS over time under the assumption of a multivariate normal 
distribution and based on mean responses in Study RM-131-009 variance -covariance structure 
(Table 14–1). A missing completely at random (MCAR) dropout rate of 20% by Week 12 was 
assumed for each treatment.
Vomiting response rates were assumed to be those observed in Study RM-131-009 (26% and 
11% for treatment and placebo respectively). Sample size was assessed using the POWER 
procedure in SAS. 
The sample size of approximately 300 participants per arm will provide more than 90% power to 
reject at least one of the primary null hypotheses using the multiplicity approach described in 
Section 10.3. 


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15.0
Statistical Software
Statistical analyses will be performed using 
 SAS on a Linux operating 
system.


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16.0
Data Handling Conventions
16.1
Visit Time Windows
Table 16.1–1 presents the visits assigned for safety analyses and the corresponding range of 
treatment days (window) during which an actual visit may occur.
Table 16.1–1.
Visit Time Windows for Safety Analysis
Derived Visit
Scheduled Test / Visit Daya
Window
Baseline
Day 1
Days ≤ 1
Visit 4
Day 14
Days [2, 21]
Visit 5
Day 28
Days [22, 43]
Visit 6
Day 56
Days [44, 71]
Visit 7
Day 84
Days ≥ 72
End of Studyb
Final or termination visit during the double-blind Treatment Period
a
Relative to the date of the first dose; Day 1 = the day of the first dose.
b
“End of Trial” will be presented in analysis tables for safety parameters, including clinical laboratory and vital signs.
If the visit date is on or after the date of the first dose of double-blind study treatment, the study 
day is calculated by visit date – date of the first dose of double-blind investigational product + 1. 
If the visit date is before the date of the first dose of double-blind investigational product, the 
study day is calculated by visit date – date of the first dose of double-blind investigational 
product. Therefore, a negative day indicates a day before the start of the double-blind 
investigational product.
If a participant has 2 or more visits within the same window, the last visit with a nonmissing 
value will be used for analysis.
16.2
Analysis Weeks and Visit Time Windows for Efficacy Analysis
16.2.1
Analysis Weeks for Efficacy Analysis
Table 16.2.1–1 below presents the analysis weeks assigned for the efficacy analysis of the 
participant daily diary data related to DGSSD. These analysis weeks will be used in the 
calculations for all week-based endpoints (eg, weekly DGSSS, weekly vomiting frequency, 
individual symptoms weekly scores etc.).


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Table 16.2.1–1.
Analysis Time 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
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 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).
16.2.2
Visit Windows for Efficacy Analysis
Visit windows as defined in Section 16.1 will be used for the analysis by visit
 


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16.4
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. If EOT assessments are repeated or unscheduled, the last 
postbaseline assessment will be used as the EOT assessment for generating summary statistics. 
However, all postbaseline assessments will be used for PCS value determination, and all 
assessments will be presented in the data listings.
16.5
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.
16.6
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.


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16.7
Missing Causal Relationship to Study Treatment for Adverse Events
If the causal relationship to the investigational product is missing for an AE that started on or 
after the date of the first dose of double-blind investigational product, a causality of yes will be 
assigned. The imputed values for causal relationship to double-blind treatment will be used for 
the incidence summary; the values will be shown as missing in the data listings.
16.8
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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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.  
16.9
Missing Date Information for Prior or Concomitant Medications
For prior or concomitant medications, excluding rescue medications, incomplete (ie, partly 
missing) start dates and/or stop dates will be imputed. When the start date and the stop date are 
both incomplete for a participant, the start date will be imputed first.
16.9.1
Incomplete Start Date
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication start date. If the stop date is complete (or imputed) and the imputed 
start date is after the stop date, the start date will be imputed using the stop date.
Missing month and day

If the year of the incomplete start date is the same as the year of the first dose of study 
treatment, the month and day of the first dose of study treatment will be assigned to the 
missing fields

If the year of the incomplete start date is before the year of the first dose of study 
treatment, December 31 will be assigned to the missing fields

If the year of the incomplete start date is after the year of the first dose of study treatment, 
January 1 will be assigned to the missing fields
Missing month only

If only the month is missing, the day will be treated as missing and both the month and 
the day will be replaced according to the above procedure
Missing day only

If the month and year of the incomplete start date are the same as the month and year of 
the first dose of study treatment, the day of the first dose of study treatment will be 
assigned to the missing day


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
If either the year of the incomplete start date is before the year of the date of the first dose 
of study treatment or if both years are the same but the month of the incomplete start date 
is before the month of the date of the first dose of study treatment, the last day of the 
month will be assigned to the missing day.

If either the year of the incomplete start date is after the year of the date of the first dose 
of study treatment or if both years are the same but the month of the incomplete start date 
is after the month of the date of the first dose of study treatment, the first day of the 
month will be assigned to the missing day
16.9.2
Incomplete Stop Date
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication stop date. If the date of the last dose of study treatment is missing, 
impute it as descripted in Section 16.4. If the imputed stop date is before the start date (imputed 
or nonimputed start date), the imputed stop date will be equal to the start date.
Missing month and day

If the year of the incomplete stop date is the same as the year of the last dose of study 
treatment, the month and day of the last dose of study treatment will be assigned to the 
missing fields

If the year of the incomplete stop date is before the year of the last dose of study 
treatment, December 31 will be assigned to the missing fields

If the year of the incomplete stop date is after the year of the last dose of study treatment, 
January 1 will be assigned to the missing fields
Missing month only

If only the month is missing, the day will be treated as missing and both the month and 
the day will be replaced according to the above procedure
Missing day only

If the month and year of the incomplete stop date are the same as the month and year of 
the last dose of study treatment, the day of the last dose of study treatment will be 
assigned to the missing day

If either the year of the incomplete stop date is before the year of the date of the last dose 
of study treatment or if both years are the same but the month of the incomplete stop date 
is before the month of the date of the last dose of study treatment, the last day of the 
month will be assigned to the missing day


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
If either the year of the incomplete stop date is after the year of the date of the last dose of 
study treatment or if both years are the same but the month of the incomplete stop date is 
after the month of the date of the last dose of study treatment, the first day of the month 
will be assigned to the missing day.
16.10
Character Values of Clinical Laboratory Parameters
If the reported value of a clinical laboratory parameter cannot be used in a statistical summary 
table because, for example, the value is a character string rather than a numerical type, a coded 
value needs to be appropriately determined and used in the statistical analyses. However, the 
actual values as reported in the database will be presented in data listings.
Table 16.10–1.
Examples for Coding of Special Character Values for Clinical Laboratory Parameters
Laboratory Test (Unit)
Possible Lab Results
(in SI units)
Coded Value for Analysis
Chemistry: ALT
< 5
0
Chemistry: AST
< 5
0
Chemistry: Bilirubin, Total
< 2
0
Urinalysis: Glucose
= OR > 55, >= 55, > 0
Positive
<= 0, Negative
Negative
Urinalysis: Ketones
= OR > 8.0, >=8.0, > 0
Positive
<= 0, Negative
Negative
Urinalysis: pH
> 8.0, >= 8.0
8.0
>= 8.5,
8.5
Urinalysis: Protein
= OR > 3.0, >=3.0, > 0
Positive
<= 0
Negative
16.11
Definition of Regions and Pooling
Geographic regions are used as randomization strata factor and include: Asia, Australia/New 
Zealand, Eastern Europe, North America, Western Europe, Latin America, Middle East and 
Africa. Depending on actual participant enrollment, the list of regions will be subject to change.  
It is expected that sample sizes will be adequately large for each strata. In case the smallest 
region has less than 8 participants with post-baseline DGSSD assessments then it will be pooled 
for purposes of analyses, with the second smallest region. If the resulting regions do not all have 
the minimum number of participants, the process will continue until the minimum number 
requirement is met. Pooling of regions -if any- will be performed prior to the study unblinding.


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RLM-MD-01/02 Statistical Analysis Plan (Amendment 2)
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17.0
Changes to Analyses Specified in Protocol
None.


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11/17/2020
18.0
References
Dmitrienko A, Tamhane A.C., Wiens, B. (2008). General multistage gate-keeping procedures. 
Biometrical Journal. 50: 667-677.
Knoke J (1991). Nonparametric Analysis of Covariance for Comparing Change in Randomized 
Studies with Baseline Values Subject to Error. Biometrics, 47(2):523-533.
Mallinckrod C., Lane P., Schnell D., Peng Y., and Mancuse J. (2008). Recommendations for the 
Primary Analysis of Continuous Endpoints in Longitudinal Clinical Trials. 42:303-319.
Ratitch B, and O’Kelly M. (2011). Implementation of Pattern-Mixture Models Using Standard 
SAS/STAT Procedures.. In Proceedings of PharmaSUG 2011 (Pharmaceutical Industry SAS 
Users Group). Paper SP04. Nashville.
Ratittch B., Lipkovich I., O’Kelly M. (2013). Combining Analysis Results from Multiple 
Imputed Categorical Data.  In Proceedings of PharmaSUG 2013 (Pharmaceutical Industry SAS 
Users Group). Paper SP03. Chicago. 
Rubin, D.B. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & Sons.
1987;75-77:169-170.


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