Open-label Extension Study of Relamorelin for the Treatment of Diabetic Gastroparesis
Phase: PHASE3
Conditions: Gastroparesis
Sponsor: Allergan

NCT03786380 
 
Study ID: Study ID: 3071-305-020 
 
Title: Open-label Extension Study of Relamorelin for the Treatment of Diabetic Gastroparesis 
 
Protocol Amendment 2 Date: 12 February 2021 

CONFIDENTIAL
Protocol 3071-305-020 Amendment 2
Relamorelin
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GRD-CLN-T-01-01 v2.0
Title Page
Protocol Title:
Open-label Extension Study of Relamorelin for the 
Treatment of Diabetic Gastroparesis 
Protocol Number:
3071-305-020
Amendment Number: 
2
Product:
Relamorelin
Brief Protocol Title:
Diabetic Gastroparesis Study 05
Development Phase:
Phase 3b
Sponsor Name and Legal Registered Addresses:
Allergan Sales, LLC, 5 Giralda Farms, Madison, NJ 
07940, United States
Allergan Ltd., Marlow International, Parkway, Marlow 
SL7 1YL, United Kingdom
Regulatory Agency Identifying Numbers: 
IND:
EudraCT:
2019-000406-30
Emergency Telephone Number:
Refer to the study contacts list
SAE Reporting Email/Fax Number:
Approval Date:
20 Dec 2019
Sponsor Signatory:
MD 
Vice President, Clinical Development-GI
The signature of the sponsor signatory is collected on the protocol approval page.
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Protocol 3071-305-020 Amendment 2
Relamorelin
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Protocol Amendment Summary of Changes
DOCUMENT HISTORY
Document
Date
Original Protocol
17 Oct 2018
Amendment 1
21 May 2019
Amendment 2 (20 Dec 2019)
Overall Rationale for the Amendment
This summary includes changes made to Protocol 3071-305-020 Amendment 1 (dated 21 May 2019). The 
purpose of this protocol amendment 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.
Changes were also made to align with the current Allergan protocol template for clarity that do not impact 
the conduct of the study.
Summary of Changes in Global Protocol Amendment 2
Section No. and Name
Description of Change
Brief Rationale
Section 1.1, Synopsis; 
Intervention Groups and 
Study Duration
Deleted reference to 2024: The study is planned 
to start enrollment of participants in December 
2018 and will end when RLM becomes 
commercially available or the sponsor terminates 
development. RLM is expected to become 
commercially available in 2024.
Section 1.2, Schema
Revised schema to reflect change of end of study
Section 1.3, Schedule of 
Activities
! Added a column heading “Study Period: Open-
Label Treatment”
! Added visit in days + visit window
! Footnote A revised as follows:
Scheduled evaluations and laboratory tests 
(hematology, clinical chemistry, and urinalysis, 
HbA1c, and pregnancy test assessments) will be 
performed every 3 months (Months 15, 18, 21, 
24, etc.) for follow-up per participant until the 
end of the study. HbA1c and pregnancy 
assessments will be performed prior to initiation 
of the study
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Section No. and Name
Description of Change
Brief Rationale
! Footnote D: Complete Physical examinations
(as per the investigator’s standard of care)
(excluding pelvic exam in women and genital 
exam in men, and rectal exam in both genders)
are to be performed at baseline, at each annual 
visit, and at the Early Termination/Final Visit (see
Section 8.2.1).
Section 4.4, End of 
Study Definition
Deleted date RLM is expected to become 
available: This study will continue until RLM 
becomes commercially available (expected in 
2024) or the sponsor terminates development.
Section 6.1, Study 
Interventions 
Administered; Table 6-1
Added a supplier:
! Baxter (prefilled cartridge)
! Allergan (assembled pen)
! Sharp (assembled pen)
Section 7, 
Discontinuation of 
Study Intervention and 
Participant 
Discontinuation/ 
Withdrawal;
Section 7.1.2 Permanent 
Discontinuation
Permanent discontinuation of study intervention 
also requires discontinuation from the study. The 
following criteria are to should be evaluated: • 
Special consideration should be paid to the 
appearance of abnormal laboratory test results 
suggesting severe drug-induced liver injury
(DILI). Discontinuation of study intervention for 
abnormal liver function should be considered by 
the investigator is required when a participant 
meets criteria for Hy’s law (see Section 8.3.7.1 
and Appendix 9 or if the investigator believes 
that it is in best interest of the participant (for 
definition see Section 8.3.7.1 and Appendix 9). 
Suggested actions and follow-up assessments for 
liver safety are provided in Appendix 9
Section 8, Study 
Assessments and 
Procedures
Scheduled evaluations and laboratory tests 
(serum chemistries and hematologic assessments,
including HbA1c and pregnancy testing) for 
each participant will be performed as noted in the
SoA (refer to Section 1.3) for up to 5 years or 
until RLM becomes commercially available or 
sponsor terminates development.
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Section No. and Name
Description of Change
Brief Rationale
Section 8.2.1, Physical 
Examinations
Complete Physical examinations (as per the 
investigator’s standard of care) (excluding 
pelvic exam in women and genital exam in men, 
and rectal exam in both genders) are to be 
performed at baseline, at each annual visit, and at 
the Final Visit. Symptom-directed (abbreviated) 
physical examinations, including evaluation of 
the injection sites for clinically significant 
reactions, may be conducted as required at other 
study visits. A clinically significant injection site 
reaction is to be reported as an AE.
Section 8.3.3, 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 AEs/SAEs and 
non-serious AESIs as defined in Appendix 3 will 
be followed until resolution, stabilization, the 
event’s etiology is otherwise explained, or the 
participant is lost to follow-up (as defined in 
Section 7.3). Further information of AE/SAE 
follow-up procedures is given in Appendix 3.
Section 8.3.7.1, 
Potential Hy’s Law
Study site personnel must record and report every 
participant who meets the criteria for potential 
Hy’s law as SAEs (see Appendix 9 for detailed 
description on handling potential Hy’s law cases 
and liver toxicity). Potential Hy’s law cases are 
also considered AESIs and Criteria for potential 
Hy’s law cases are as follows: 
• ALT or AST ≥ 3 × ULN) AND 
• Total bilirubin ≥ 2 × ULN AND 
• Alkaline phosphatase < 2 × ULN
Study site personnel must record and report 
every participant who meets the criteria for 
potential Hy’s law as SAEs (see Appendix 9 for 
detailed description on handling potential Hy’s 
law cases and liver toxicity). 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 last dose of study 
intervention.
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Section No. and Name
Description of Change
Brief Rationale
Section 9.6, Data 
Monitoring Committee
Data Monitoring Committee section was added
along with the following text: A Data Monitoring 
Committee was not used for this study.
Section 10.1.10/
Appendix 1,
Compliance with 
Protocol
Compliance with Protocol section added along 
with the following text: The investigator is 
responsible for compliance with the protocol at 
the investigational site. A representative of the 
sponsor will make frequent contact with the 
investigator and his/her research staff and will 
conduct regular monitoring visits at the site to 
review participant and study intervention 
accountability records for compliance with the 
protocol. Protocol deviations will be discussed 
with the investigator upon identification. 
Significant protocol deviations will be reported 
to the IRB/IEC according to the IRB/IEC’s 
reporting requirements.
Section 10.2/
Appendix 2, Clinical 
Laboratory Tests/ 
Table 10-1, Protocol-
Required Safety 
Laboratory Assessments
Other Screening Tests was amended to read: 
Urine human chorionic gonadotropin (hCG) 
pregnancy test (at Baseline as noted in the SoA) 
as needed for women of childbearing potential 
will be performed every 3 months as specified in 
the SoA.
Section 10.3.1/
Appendix 3, Definition 
of AE; AE of Special 
Interest (AESI)
Serious AESIs should must be reported to the 
sponsor within 24 hours via the SAE form. 
Nonserious AESIs do not require submission on 
an SAE form; should be recorded on the 
appropriate page of the eCRF.
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Section No. and Name
Description of Change
Brief Rationale
Section 10.3.4/Appendix 
3, Reporting of SAEs
Revise subsection tabular information to read: 
SAE Reporting to Sponsor or Designee Within 
24 Hours
Section 10.7/
Appendix 7,
Contraceptive Guidance 
and Collection of 
Pregnancy Information; 
Pregnancy Testing
!
WOCBP are should only to be included in 
the study after a confirmed menstrual period and 
a negative urine pregnancy test.
Section 19.9/
Appendix 9, Liver 
Safety: Suggested 
Actions and Follow-up 
Assessments
Entire appendix has been revised.
Section 10.10/
Appendix 10, Protocol 
Amendment History
Moved Summary of Changes text in Amendment 
1 to appendices 
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Table of Contents
Title Page ........................................................................................................................................1
Protocol Amendment Summary of Changes...............................................................................2
Table of Contents...........................................................................................................................7
List of Tables ................................................................................................................................11
1.
Protocol Summary........................................................................................................12
1.1.
Synopsis..........................................................................................................................12
1.2.
Schema............................................................................................................................14
1.3.
Schedule of Activities.....................................................................................................15
2.
Introduction...................................................................................................................17
2.1.
Study Rationale...............................................................................................................18
2.2.
Background.....................................................................................................................19
2.3.
Benefit/Risk Assessment ................................................................................................21
3.
Objectives and Endpoints ............................................................................................22
4.
Study Design..................................................................................................................22
4.1.
Overall Design................................................................................................................22
4.1.1.
Clinical Hypotheses ........................................................................................................22
4.2.
Scientific Rationale for Study Design ............................................................................22
4.3.
Justification for Dose......................................................................................................23
4.4.
End of Study Definition..................................................................................................23
5.
Study Population...........................................................................................................24
5.1.
Inclusion Criteria ............................................................................................................24
5.2.
Exclusion Criteria ...........................................................................................................24
5.3.
Lifestyle Considerations .................................................................................................25
5.4.
Screen Failures................................................................................................................25
6.
Study Intervention........................................................................................................25
6.1.
Study Interventions Administered ..................................................................................25
6.1.1.
Study Supplies ................................................................................................................27
6.2.
Preparation/Handling/Storage/Accountability................................................................27
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................28
6.4.
Study Intervention Compliance ......................................................................................28
6.5.
Concomitant Therapy .....................................................................................................28
6.5.1.
Prohibited Interventions..................................................................................................28
6.5.2.
Permitted Interventions...................................................................................................29
6.5.3.
Rescue Medicine.............................................................................................................29
6.6.
Dose Modification ..........................................................................................................29
6.7.
Intervention after the End of the Study...........................................................................29
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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................30
7.1.
Discontinuation of Study Intervention............................................................................30
7.1.1.
Temporary Discontinuation ............................................................................................30
7.1.2.
Permanent Discontinuation.............................................................................................31
7.2.
Participant Discontinuation/Withdrawal from the Study................................................31
7.3.
Lost to Follow-Up...........................................................................................................32
8.
Study Assessments and Procedures.............................................................................32
8.1.
Efficacy Assessments .....................................................................................................33
8.2.
Safety Assessments.........................................................................................................33
8.2.1.
Physical Examinations....................................................................................................34
8.2.2.
Vital Signs.......................................................................................................................34
8.2.3.
Electrocardiograms .........................................................................................................35
8.2.4.
Clinical Safety Laboratory Assessments ........................................................................35
8.2.5.
Self-monitoring of Blood Glucose..................................................................................36
8.3.
Adverse Events and Serious Adverse Events .................................................................36
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................36
8.3.2.
Method of Detecting AEs and SAEs ..............................................................................37
8.3.3.
Follow-up of AEs and SAEs...........................................................................................37
8.3.4.
Regulatory Reporting Requirements for SAEs...............................................................38
8.3.5.
Pregnancy........................................................................................................................38
8.3.6.
Medical Device Incidents (Including Malfunctions)......................................................38
8.3.6.1. Time Period for Detecting Medical Device Incidents ....................................................39
8.3.6.2. Follow-up of Medical Device Incidents .........................................................................39
8.3.6.3. Prompt Reporting of Medical Device Incidents to Sponsor...........................................39
8.3.6.4. Regulatory Reporting Requirements for Medical Device 
Incidents and Deficiencies..............................................................................................39
8.3.7.
Adverse Events of Special Interest .................................................................................40
8.3.7.1. Potential Hy’s Law .........................................................................................................40
8.3.7.2. Inadequate Control of Diabetes: Hyperglycemia and 
Hypoglycemia.................................................................................................................40
8.3.8.
Medication Errors ...........................................................................................................41
8.4.
Treatment of Overdose ...................................................................................................41
8.5.
Pharmacokinetics............................................................................................................42
8.6.
Pharmacodynamics .........................................................................................................42
8.7.
Genetics ..........................................................................................................................42
8.8.
Biomarkers......................................................................................................................42
8.9.
Health Economics...........................................................................................................42
9.
Statistical Considerations.............................................................................................42
9.1.
Statistical Hypothesis......................................................................................................42
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9.2.
Sample Size Determination ............................................................................................42
9.3.
Population for Analyses..................................................................................................42
9.4.
Statistical Analyses.........................................................................................................43
9.4.1.
Safety Analyses...............................................................................................................43
9.4.1.1. Adverse Events ...............................................................................................................44
9.4.1.2. Clinical Laboratory Assessments....................................................................................44
9.4.1.3. Vital Signs.......................................................................................................................45
9.4.1.4. Electrocardiogram...........................................................................................................45
9.5.
Interim Analyses.............................................................................................................45
9.6.
Data Monitoring Committee...........................................................................................45
10.
Supporting Documentation and Operational Considerations..................................46
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................46
10.1.1.
Regulatory and Ethical Considerations...........................................................................46
10.1.2.
Financial Disclosure........................................................................................................46
10.1.3.
Informed Consent Process ..............................................................................................47
10.1.4.
Data Protection................................................................................................................48
10.1.5.
Posting Clinical Study Data............................................................................................49
10.1.6.
Data Quality Assurance ..................................................................................................49
10.1.7.
Source Documents ..........................................................................................................49
10.1.8.
Study and Site Closure....................................................................................................50
10.1.9.
Publication Policy...........................................................................................................50
10.1.10. Compliance with Protocol...............................................................................................51
10.2.
Appendix 2: Clinical Laboratory Tests...........................................................................52
10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................................53
10.3.1.
Definition of AE .............................................................................................................53
10.3.2.
Definition of SAE ...........................................................................................................55
10.3.3.
Recording and Follow-Up of AE and/or SAE................................................................56
10.3.4.
Reporting of SAEs..........................................................................................................58
10.4.
Appendix 4: Abbreviations.............................................................................................59
10.5.
Appendix 5: Standard Discontinuation Criteria..............................................................61
10.6.
Appendix 6: Study Tabular Summary............................................................................62
10.7.
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................63
10.8.
Appendix 8: Medical Device Incidents: Definition and 
Procedures for Recording, Evaluating, Follow-up, and Reporting.................................67
10.8.1.
Definitions of a Medical Device Incident.......................................................................67
10.8.2.
Documenting Medical Device Incidents.........................................................................68
10.9.
Appendix 9: Liver Safety: Suggested Actions and Follow-up 
Assessments....................................................................................................................69
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11.
References......................................................................................................................79
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List of Tables
Table 6-1
Study Intervention Details................................................................................. 26
Table 9-1
Analysis Populations......................................................................................... 42
Table 10-1
Protocol-Required Safety Laboratory Assessments.......................................... 52
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1.
Protocol Summary
1.1.
Synopsis
Protocol Title: Open-label Extension Study of Relamorelin for the Treatment of Diabetic 
Gastroparesis 
Protocol Number: 3071-305-020
Brief Title: Diabetic Gastroparesis Study 05
Study Phase: Phase 3b
Study Rationale:
Previous Phase 2 studies have provided evidence that RLM may be a safe and effective treatment 
for participants with DG.
GP is 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 duodenum and small intestine takes longer than normal and occurs with
unpredictable timing. DM, either Type 1 or Type 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.
The pharmacodynamic effect of RLM on gastric emptying was confirmed, and the beneficial
effects on the symptoms of DG were observed in the Phase 2b study, RM-131-009. Efficacy, 
safety, and tolerability of RLM are under investigation in Phase 3 studies, including long-term 
efficacy and safety studies conducted for up to 12 months’ duration. 
A significant unmet medical need exists for a safe and effective treatment of patients with DG 
whose quality of life is negatively impacted by their disease and for whom the current standard of
care is suboptimal. While waiting for regulatory assessment of the results in the Phase 3 studies, 
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the sponsor is planning to provide access to RLM to participants with DG who have completed 
double-blind treatment in the Phase 3 program (Studies RLM-MD-03 and RLM-MD-04). 
The objective of Study 3071-305-020 is to assess the safety of RLM in participants with DG who 
have previously completed the Phase 3 studies, RLM-MD-03 or RLM-MD-04. Safety 
assessments include AEs, clinical laboratory values, vital signs, and ECGs (reported as clinically 
significant AEs). No endpoints were specified for this study.
Overall Study Design:
Study 3071-305-020 is an open-label, multicenter, multinational safety study in participants with 
DG who completed the Phase 3 studies, RLM-MD-03 or RLM-MD-04. Participants who 
discontinued Studies RLM-MD-03 or RLM-MD-04 for any reason are not to be enrolled into this 
study. Participants who roll over to this continued-access study within 30 days (ie, ≤30 days) of 
completing their final visit assessments in either Study RLM-MD-03 or Study RLM-MD-04 do 
not need to complete baseline assessments; information from the final visit of 
Studies RLM-MD-03 or RLM-MD-04 will be used as the information for Visit 1 of this study. 
Visit 1 should occur in ≤30 days of the last visit of the lead-in study. If a participant enters this 
continued-access study > 30 days after last visit in either lead-in study, Visit 1 baseline 
assessments will be completed as shown in Section 1.3.
Approximately 1000 participants may roll over from Studies RLM-MD-03 or RLM-MD-04 at 
approximately 700 sites with an anticipated attrition rate of approximately 20% per year. No 
participant replacement is planned in this continued-access, open-label study.
Number of Sites:
Approximately 700 study sites that participated in Studies RLM-MD-03 or RLM-MD-04 will have 
the option to participate in the continued-access, open-label study.
Intervention Groups and Study Duration:
The study is planned to start enrollment of participants in December 2018 and will end when 
RLM becomes commercially available or the sponsor terminates development. 
Data Monitoring Committee: No
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1.2.
Schema
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2.
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 DG. 
Ghrelin, a 28 amino-acid peptide, is produced predominantly by specialized cells of the stomach 
and pancreas. Ghrelin has been demonstrated to be a central modulator of energy homeostasis. It 
is the natural ligand for the 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 2004; 
Trudel 2003; and Murray 2005). It can increase body weight, attributed to a combination of 
enhanced food intake, increased GE, and increased food assimilation, coupled with a transient 
increase in growth hormone, which promotes nutrient incorporation into tissues.
RLM 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 2015; 
Acosta 2016). 
GP is a disorder characterized 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. 
DM, either Type 1 or Type 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, and
negatively affect function (Parkman 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 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 2011; Parkman 2011). Serious adverse sequelae of DG 
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include: potentially life-threatening dehydration due to persistent vomiting, 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 (US Department of 
Health and Human Services 2012). Aside from the impact on patients, these events often lead to 
hospitalization (Koch 2016), resulting in a high economic burden for health care systems. 
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 2001). As a result, diabetic patients with DG often have poorly controlled 
diabetes, frequently with alternating hypo- and hyperglycemia, especially if treated with insulin. 
Little data on the incidence and prevalence of GP are available; however, an older epidemiology 
study of diagnosed GP (defined as typical symptoms plus confirmed delayed GE by 
scintigraphy) 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 2009). This study 
reported that age-adjusted prevalence of GP was approximately 4 times greater for women than 
men (37.8 vs 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 prevalence 
of obesity.
2.1.
Study Rationale
Previous Phase 2 studies have provided evidence that RLM may be a safe and effective treatment 
for patients with DG.
GP is 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 duodenum and small intestine takes longer than normal and occurs with
unpredictable timing. DM, either Type 1 or Type 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
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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.
The PD effect of RLM on gastric emptying was confirmed, and the beneficial effects on the
symptoms of DG were observed in the Phase 2b study, RM-131-009. Efficacy, safety, and
tolerability of RLM are under investigation in Phase 3 studies, including long-term efficacy and 
safety studies conducted for up to 12 months’ duration. 
A significant unmet medical need exists for a safe and effective treatment of patients with DG 
whose quality of life is negatively impacted by their disease and for whom the current standard of
care is suboptimal. While waiting for regulatory assessment of the results in the Phase 3 studies, 
the sponsor is planning to provide access to RLM to participants with DG who have completed 
double-blind treatment in the Phase 3 program (Studies RLM-MD-03 and RLM-MD-04). 
The objective of Study 3071-305-020 is to assess the safety of RLM in participants with DG who 
have previously completed the Phase 3 studies, RLM-MD-03 or RLM-MD-04. Safety 
assessments include AEs, clinical laboratory values, vital signs, and ECGs (reported as clinically 
significant AEs). No endpoints were specified for this study.
2.2.
Background
RLM 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 RLM for the treatment of DG in adults. RLM is a member of an established class 
of compounds, ghrelin agonists, but if granted regulatory approval, it will be the first member of 
this class to attain marketing approval for DG.
In completed clinical studies to date, 466 participants with T1DM or T2DM with DG have been 
exposed to RLM at doses up to 100 μg administered BID by SC injection for up to 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 RLM. GE was 
accelerated and RLM 10 μg BID significantly decreased the vomiting severity score and mean 
number of weekly vomiting episodes in participants with vomiting at baseline and produced 
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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) compared with placebo. The safety and tolerability profile of RLM in 
Study RM-131-004 was generally good. 
Study RM-131-009 was a randomized, double-blind, placebo-controlled, stratified, 
multiple-dose, multinational study with 10 μg BID, 30 μg BID, and 100 μg BID doses of RLM. 
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 target participant population for 
enrollment in the Phase 2b Study RM-131-009 (DG participants with vomiting at baseline) and 
encouraged assessment of a wider range of RLM doses was based on results from 
Study RM-131-004.
Results from Study RM-131-009 showed a statistically significant effect of RLM over placebo 
on GE for the 10 μg and 30 μg doses. Vomiting episodes were reduced from baseline to 
Week 12 by approximately 75% in all RLM 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 RLM advantage. 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 RLM compared with 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 (Camilleri 2017). 
RLM 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 RLM compared with
placebo; hypoglycemia was infrequently reported (only 1.0% incidence in the placebo group and 
1.2% in the RLM 100 μg group). Twenty-three SAEs were reported in the 289 participants 
treated with the 3 doses of RLM 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 comorbidities. Only 2 of 
the SAEs (cardiac failure congestive and DM inadequate control) were assessed by the 
investigator as possibly related to study treatment, both in the 100-μg treatment group. Three 
AEs of diabetic ketoacidosis were reported, 1 event on each RLM dose. A total of 
20 RLM-treated participants and 3 placebo-treated participants discontinued study treatment due 
to an AE, only 3 of which were in the RLM 10 μg BID group.
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With respect to laboratory findings, in some participants, glycemic control appeared to be 
negatively affected by treatment with RLM. There were trends in increasing HbA1c values after 
the initiation of RLM, which changed little 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, ECGs, physical examination findings, and 
injection site reactions; anti-drug antibodies were not found.
A detailed description of the chemistry, pharmacology, efficacy, and safety of RLM is provided 
in the investigator’s brochure (Relamorelin Investigator’s Brochure).
2.3.
Benefit/Risk Assessment
Based on RLM information 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 are in 
place, including special laboratory assessments to allow early recognition by investigators and 
participants of a change of glycemic control. Thus, blood glucose and HbA1c assessments are 
included in this protocol so that action (eg, adjustment of medication and diet) may be taken, if 
necessary, to maintain stable glucose levels while participants are self-administering RLM. This, 
however, might increase the incidence of hypoglycemic reactions, especially in participants with 
T1DM. Participants’ self-monitoring of glucose levels using glucometers is expected to alert 
participants and investigators to the possibility of hypoglycemic events as well. See Section 4, 
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 RLM treatment may be found in the investigator’s brochure 
(Relamorelin Investigator’s Brochure); the Investigational Directions for Use for the pen 
injector, the device that will be used to administer study intervention, is also provided.
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3.
Objectives and Endpoints
Objectives
Endpoints/Assessments
Primary
!
To assess the safety of continued treatment with
RLM for participants who previously completed the 
RLM-MD-03 or RLM-MD-04 study
!
No endpoints were specified for this study. 
Safety assessments include: AEs, clinical 
laboratory values, vital signs, ECGs (reported 
as clinically significant AEs)
4.
Study Design
4.1.
Overall Design
Study 3071-305-020 is an open-label, multicenter, multinational safety study in participants with 
DG who completed the Phase 3 studies, RLM-MD-03 or RLM-MD-04, and have no ongoing 
AEs from either lead-in study that, in the investigator’s opinion, would preclude participation. 
Participants who discontinued Studies RLM-MD-03 or RLM-MD-04 for any reason are not to be 
enrolled into this study. Participants who roll over to this continued access study within 30 days 
(ie, ≤30 days) of completing their final visit assessments in either Study RLM-MD-03 or 
Study RLM-MD-04 do not need to complete baseline assessments; information from the final 
visit of Studies RLM-MD-03 or RLM-MD-04 will be used as the information for Visit 1 of this 
study (see Section 8). Visit 1 should occur in ≤30 days of the last visit of the lead-in study. If a 
participant enters this continued-access study > 30 days after last visit in either lead-in study, 
Visit 1 baseline assessments will be completed as shown in Section 1.3
Approximately 1000 participants may roll over from Studies RLM-MD-03 or RLM-MD-04 at 
approximately 700 sites with an anticipated attrition rate of approximately 20% per year. No 
participant replacement is planned in this continued-access, open-label study.
4.1.1.
Clinical Hypotheses
There is no specific clinical hypothesis related to the efficacy of treatment. 
4.2.
Scientific Rationale for Study Design
The Phase 3 studies will provide placebo-controlled information on the safety and efficacy of 
RLM in the treatment of DG. This open-label continuation of treatment will provide additional 
information on the long-term safety of RLM. The current study , will provide sufficient long-
term safety information to support the safe use of RLM as a chronic treatment of DG.
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4.3.
Justification for Dose
A RLM dose of 10 μg SC BID will be used, which is the same as the dose in the Phase 3 
program.
This dose was selected based on clinical safety and efficacy data from Study RLM-131-009, 
which also provided PK and PD information for the 10 μg 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 RLM 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 Study 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 RLM tested 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 effects, while the 10 μg BID 
dose achieved near maximal reductions. Of note, the twice-a-day regimen of RLM appears to be 
necessary for effective symptom relief; the 10 μg once daily study treatment did not demonstrate 
significant improvement in symptom relief compared with placebo after 28 days of dosing in 
Study RM-131-004.
Review of the safety laboratory data collected in RM-131-009 revealed a 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 an increase in HbA1c values that was 
approximately twice as much as observed for the 10 μg BID dose after 12 weeks of study. 
Shorter durations of treatment (4 weeks) with 10 μg BID of RLM, as observed in 
Study RM-131-004, did not demonstrate this increase in HbA1c in diabetic participants.
4.4.
End of Study Definition
This study will continue until RLM becomes commercially available or the sponsor terminates 
development. 
A participant is considered to have completed the study if he/she has completed a final visit
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5.
Study Population
The target population is adult participants with DG who have successfully completed
Study RLM-MD-03 or RLM-MD-04. Prospective approval of protocol deviations to enrollment 
criteria, also known as protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
1. Successful completion of either Study RLM-MD-03 or Study RLM-MD-04 (completed 
final study visit), and rolling over into Study 3071-305-020 in ≤30 days; eligible 
participants who completed these studies prior to administrative initiation of this protocol 
at their study center, will also be allowed to participate in this continued-access study
2. Ability to provide written IC prior to any study procedures and willingness and ability to 
comply with study procedures
3. Demonstration of adequate compliance with the study procedures in Study RLM-MD-03 
or RLM-MD-04, in the opinion of the investigator
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Participant is planning to receive an investigational drug (other than study intervention) 
or investigational device at any time during Study 3071-305-020.
2. Participant has an unresolved AE from a lead-in study that, in the investigator’s opinion, 
would limit the participant’s ability to participate in the study (see also Section 8).
3. Any other reason that, in the investigator’s opinion, would confound proper interpretation 
of the study or expose a participant to unacceptable risk, including renal, hepatic, or 
cardiopulmonary disease
4. Females who are pregnant, nursing, or planning a pregnancy during the study
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5. Participant is directly or indirectly involved in the conduct and administration of this 
study as an investigator, sub-investigator, study coordinator, other study staff member, or 
employee of Allergan; or the participant is a first-degree family member, significant 
other, or relative residing with one of the above persons involved directly or indirectly in 
the study; or the participant is enrolled in this study at another clinical study site.
Rationale for Inclusion and Exclusion Criteria
The inclusion and exclusion criteria are meant to create a population of participants that is well 
characterized as having DG with symptoms that require chronic treatment.
5.3.
Lifestyle Considerations
There are no specific dietary restrictions in the study. It is expected that participants are aware of 
the importance of maintaining reasonable consistency in treating DM and maintaining healthy 
lifestyle and dietary restrictions for achieving adequate control of hyperglycemia.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study.
Individuals who do not meet the criteria for participation in this study (screen failures) may not
be rescreened.
6.
Study Intervention
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol.
The only study intervention planned is the daily administration of RLM 10 μg SC BID. 
6.1.
Study Interventions Administered
Participants are to self-administer open-label study intervention SC BID with the first daily dose 
being administered within approximately 30 minutes before the morning meal (ie, breakfast at 
approximately 08:00) and the second daily dose within approximately 30 minutes before the 
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evening meals, study intervention is to be administered during typical meal times 
(eg, 06:00 to 09:00 and 17:00 to 20:00). 
If a participant misses a dose before either the morning or evening meal, he/she is to adjust 
his/her study intervention administration as follows:
!
If within 6 hours of the normal dosing time relative to the morning or evening dose, the 
participant is to self-administer the dose at that time.
!
If more than 6 hours after the normal dosing time relative to the morning or evening dose, 
the participant is not to self-administer the dose, and should resume normal dosing at the 
next scheduled time (ie, that evening if the morning dose was missed, or the next 
morning if the evening dose was missed).
Participants are to rotate injection sites in the abdomen. 
Study intervention will be dispensed as pen injectors with prefilled cartridges of RLM. Study 
intervention details are provided in Table 6-1.
Table 6-1
Study Intervention Details
Study Intervention
RLM
Dosage Formulation
Prefilled cartridge in multi-dose pen injector
Unit Dose Strength
10 μg dose
Route of Administration
SC
Dosing Instructions
Administer twice daily
Packaging and Labeling
Study intervention will be provided in a single unit carton. Each carton will be 
labeled as required per country requirement.
Manufacturer
Baxter (prefilled cartridge)
Allergan (assembled pen)
Sharp (assembled pen)
Injection Device
Utilize multi-dose pen injector for the administration of the study intervention. 
Refer to the Relamorelin Pen Investigational Directions for Use for detailed 
instructions on use of the injection device.
Each pen injector is to be used for 28 days.
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6.1.1.
Study Supplies
1. The Allergan-manufactured medical devices (or devices manufactured for Allergan by a 
third party) provided for use in this study are: (1) prefilled cartridge, and (2) multi-dose 
pen injector.
2. Instructions for medical device use are provided in the 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 
Section 8.3.6).
4. Other medical devices (not manufactured by or for Allergan) provided for use in this study 
may include a glucometer.
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Reference Manual.
5. Devices that are damaged during shipment or at the site or that malfunction during use 
must be accounted for and returned. The investigator will promptly notify the sponsor’s 
Clinical Research department of any device malfunction. The Clinical Research or 
Product Support representative will provide instruction for the return of any faulty device 
for evaluation.
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6.3.
Measures to Minimize Bias: Randomization and Blinding
This is an open-label study. No blinding of assigned study intervention will occur.
6.4.
Study Intervention Compliance
Study intervention compliance will be assessed using participant recall during each study visit. 
The study centers will keep an accurate drug disposition record that specifies study intervention 
dispensed to each participant and the date of dispensing.
6.5.
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 eCRF along with:
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency
Prior medications that were ongoing at the end of Studies RLM-MD-03 and RLM-MD-04 will 
be automatically transferred into the Study 3071-305-020 database.
As much as possible, the dose and frequency of all concomitant medications taken for chronic 
conditions with the exception of DM are to be held stable during the study. The sponsor is to be 
contacted if there are any questions regarding concomitant or prior therapy. Diabetic medications 
will be adjusted as needed to keep glycemic control at a steady level (Section 6.5.2).
6.5.1.
Prohibited Interventions
There are no prohibited drug classes in this study. However, some drugs, eg, GLP-1 agonists, 
pramlintide or opioid drugs, may slow GE and may be undesirable in participants with DG. 
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6.5.2.
Permitted Interventions
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving during the study must be recorded on 
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 consist mostly of participants receiving 1 or more 
prescription medications for blood-glucose control, as needed. 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. Certain diabetic 
drugs delay GE and are not expected to benefit participants with DG. Other therapy considered 
necessary for the participant’s welfare may be given at the discretion of the investigator or 
participant’s health care provider. 
The sponsor or designee is to be contacted if there are any questions regarding concomitant 
therapy.
6.5.3.
Rescue Medicine
There is no restriction on the use of medications to alleviate symptoms of DG such as nausea and 
vomiting. The use of such treatment and its frequency are to be recorded on the concomitant 
medications eCRF.
6.6.
Dose Modification
No dose modifications are planned.
6.7.
Intervention after the End of the Study
No interventions are planned after closure of the study.
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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
A premature discontinuation will occur if a participant who signs the ICF and is dosed with study 
intervention ceases participation in the study, regardless of circumstances, before the completion 
of the protocol-defined study procedures.
Definitions of the standard terms that may lead to discontinuations are provided in Appendix 5.
Reasons for discontinuation from the study intervention and/or the study may include the 
following commonly used or other acceptable terms:
Commonly Used Terms
Other Acceptable Terms
Adverse event
Death
Completed
Disease relapse
Lack of efficacy
Failure to meet entry criteria
Lost to follow-up
Progressive disease
Other
Technical problems
Physician decision
Pregnancy
Protocol deviation
Site terminated by sponsor
Study terminated by sponsor
Withdrawal by subject
7.1.
Discontinuation of Study Intervention
7.1.1.
Temporary Discontinuation 
In the event of AE or intercurrent illness, dosing of study intervention can be stopped
temporarily for a maximum duration of 14 days. If longer cessation of dosing is necessary, the 
investigator must contact the sponsor.
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7.1.2.
Permanent Discontinuation
Permanent discontinuation of study intervention also requires discontinuation from the study. 
The following criteria should be evaluated:
!
Special consideration should be paid to the appearance of abnormal laboratory test results 
suggesting severe drug-induced liver injury (DILI). Discontinuation of study intervention
for abnormal liver function should be considered by the investigator when a participant 
meets criteria for Hy’s law (see Section 8.3.7.1 and Appendix 9) or if the investigator 
believes that it is in the best interest of the participant.
!
Documented episode of diabetic ketoacidosis, hyperosmolar non-ketotic diabetic 
syndrome, or severe hypoglycemia (defined as glucose levels < 3mmol/L, or < 54 mg/dl) 
that are assessed as study treatment-related.
!
Female participants who become pregnant during the study must be discontinued from 
study intervention immediately and withdrawn from the study. See Appendix 7 for further 
details regarding follow-up of the participant through the pregnancy.
See the SoA (Section 1.3) for data to be collected at the time of study intervention
discontinuation.
7.2.
Participant Discontinuation/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.
!
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 and follow-up and 
for any further evaluations that need to be completed.
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7.3.
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 ought to 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 will be documented in the participant’s 
medical record.
!
If the participant continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
8.
Study Assessments and Procedures
Scheduled evaluations and laboratory tests (serum chemistries and hematologic assessments, 
including HbA1c and pregnancy testing) for each participant will be performed as noted in the 
SoA (refer to Section 1.3).
A central laboratory will be used for safety laboratory assessments. Safety data as well as central 
laboratory results will be collected as noted in the SoA. 
!
Study procedures and their timing are summarized in the SoA (Section 1.3).
!
Protocol waivers or exemptions are not allowed.
!
Immediate safety concerns are to be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant will continue or discontinue study
intervention.
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!
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
!
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will be approximately
170 mL. Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
All participants who roll over to this continued-access study (Study 3071-305-020) after
completing their final visit assessments in either Study RLM-MD-03 or Study RLM-MD-04 are 
required to sign a new IC. Additionally, eligible participants who completed these studies prior 
to administrative initiation of this protocol at their study center, will be allowed to participate in
this continued-access study, but are required to sign a new IC. Information from the final visit of 
Study RLM-MD-03 or Study RLM-MD-04 will be used as the information for Visit 1 (Baseline) 
of this study for these participants; if a participant enters this continued-access study > 30 days
after last visit in lead-in study, Visit 1 baseline assessments will be completed (See SoA, 
Section 1.3). Demography and ongoing medical history will also be rolled over from Studies 
RLM-MD-03 or RLM-MD-04.
8.1.
Efficacy Assessments
No efficacy assessments are planned for this continued-access study. 
8.2.
Safety Assessments
Safety assessments will include vital signs, clinical laboratory tests (hematology, clinical 
chemistry including HbA1c, urinalysis), and ECG values reported as clinically significant AEs.
AEs, including SAEs, SUSARs, and study-intervention discontinuation due to AEs will be
assessed.
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3).
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8.2.1.
Physical Examinations
!
Physical examinations (as per the investigator’s standard of care) are to be performed at 
baseline, at each annual visit, and at the Final Visit. Symptom-directed (abbreviated) 
physical examinations, including evaluation of the injection sites for clinically significant 
reactions, may be conducted as required at other study visits. A clinically significant 
injection site reaction is to be reported as an AE.
!
Any abnormality noted on the physical examination done at Final Study Visit or the Early 
Termination Visit that was not present on the physical examination at baseline is to be 
reported as an AE if considered by the investigator to be clinically significant.
!
Investigators are to pay special attention to clinical signs related to previous serious 
illnesses.
8.2.2.
Vital Signs
Vital signs will be assessed as follows:
!
Systolic and diastolic BP, HR, temperature, and respiratory rate will be assessed at 
baseline, at each annual visit, and at the Final/Early Termination Visit; BP and HR will be 
assessed at all other visits; 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 are to be preceded by at least 3 minutes of rest for the 
participant in a quiet setting without distractions (eg, television, cell phones).
!
Vital signs are to be taken before blood collection for laboratory tests. 
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8.2.3.
Electrocardiograms
!
Single 12-lead ECG will be obtained at baseline from a lead-in study, at Week 2 (Visit 1a), 
yearly starting at Visit 5 (Month 12), and at the Final Visit. If a participant enters the 
continued-access study > 30 days after last visit in lead-in study, an ECG will be obtained 
at Visit 1 as part of the baseline assessments for the continued-access study. All 
participants will have an ECG at Week 2 (Visit 1a). If a participant continues in the study 
for longer than 1 year, ECGs are to be performed annually starting at Visit 5. Any 
clinically significant changes in ECG results should be reported as AEs.
8.2.4.
Clinical Safety Laboratory Assessments
!
See Appendix 2 for the list of laboratory tests to be performed and the SoA (Section 1.3)
for the timing and frequency.
!
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE eCRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
!
All laboratory tests with abnormal values considered clinically significant during 
participation in the study or within 30 days after the last dose of study intervention must 
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 is to 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 (Section 1.3).
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, then the results must be recorded 
in the eCRF as AEs/SAEs.
o
Urine dipstick kits are to be used to conduct pregnancy tests.
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8.2.5.
Self-monitoring of Blood Glucose
Participants will be strongly encouraged to perform self-monitoring of blood glucose at home in 
order to achieve and maintain optimum glucose control during the study. This is almost always 
required for participants with T1DM and is good clinical practice in participants with T2DM. It 
is recommended that this be done at least once weekly. 
Information from blood glucose self-monitoring, in addition to that provided by values of HbA1c 
and fasting blood glucose, will be available to investigators for decision-making regarding 
adjustment of diabetic medications, diet, and exercise (or, alternatively, for decision-making 
regarding referral of the participant to his/her health care provider for the same purpose). 
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant or noted by the investigator.
The investigator and any qualified 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 intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7.1).
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All AEs and SAEs will be collected from the signing of the ICF until 30 days after the final visit 
in the study, or early termination visit, at the timepoints specified in the SoA (Section 1.3), and 
as observed or reported spontaneously by study participants.
Medical occurrences that begin before the start of study intervention, but after obtaining IC will 
be recorded on the AE eCRF.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 3. 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 information after conclusion of the 
study participation. However, if the investigator learns of any SAEs, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
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reasonably related to the study intervention or study participation, the investigator must promptly 
notify the sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
8.3.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3.
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 AEs/SAEs and non-serious AESIs as defined in Appendix 3
will be followed until resolution, stabilization, the event’s etiology is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). Further information on AE/SAE 
follow-up procedures is given in Appendix 3.
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by MSP to elucidate the 
nature and/or causality of the AE or SAE as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals.
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide the MSP with a copy of any postmortem findings including 
histopathology.
New or updated information will be recorded on the originally completed eCRF.
The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information.
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8.3.4.
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention 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 intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.
!
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
!
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) 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.
8.3.5.
Pregnancy
!
Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until 7 days after the last dose.
!
If a pregnancy is reported, the investigator must inform the sponsor within 24 hours of 
learning of the pregnancy and must follow the procedures outlined in Appendix 7.
!
Abnormal pregnancy outcomes (eg, spontaneous or elective abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.6.
Medical Device Incidents (Including Malfunctions)
Medical devices are being provided for use in this study for self-administration of study 
intervention. To fulfill regulatory reporting obligations worldwide, the investigator is responsible 
for the detection and documentation of events meeting the definitions of incident, deficiency, or 
malfunction that occur during the study with such devices.
The definition of a medical device incident and a device deficiency can be found in Appendix 8.
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Incidents fulfilling the definition of an AE/SAE will also follow the processes outlined in 
Section 8.3.3 and Appendix 3 of the protocol.
8.3.6.1.
Time Period for Detecting Medical Device Incidents
!
Medical device incidents, deficiencies, 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 8.
8.3.6.2.
Follow-up of Medical Device Incidents
!
All medical device incidents involving an AE/SAE will be followed and reported in the 
same manner as other AEs (see Section 8.3.3). This applies to all participants, including 
those who discontinue study intervention or the study.
!
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident.
!
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator.
8.3.6.3.
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.
8.3.6.4.
Regulatory Reporting Requirements for Medical Device Incidents and 
Deficiencies
!
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 to 
notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies.
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!
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.
8.3.7.
Adverse Events of Special Interest
8.3.7.1.
Potential Hy’s Law
Criteria for potential Hy’s law cases are as follows: 
!
ALT or AST ≥3 × ULN) AND 
!
Total bilirubin ≥2 × ULN AND 
!
Alkaline phosphatase < 2 × ULN
Study site personnel must record and report every participant who meets the criteria for potential 
Hy’s law as SAEs (see Appendix 9 for detailed description on handling potential Hy’s law cases 
and liver toxicity). 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 last dose of study 
intervention. 
Additional details regarding liver safety assessments and follow-up are provided in Appendix 9.
8.3.7.2.
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 must 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 are to be reported 
as AEs (Section 8.3.3). 
Documented episode of diabetic ketoacidosis, hyperosmolar non-ketotic diabetic syndrome, or 
severe hypoglycemia (defined as glucose levels < 3mm/L, or < 54 mg/dl) that are assessed as 
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8.3.8.
Medication Errors
Medication error refers to any unintended error in the dosing and/or administration of the study 
intervention 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 intervention.
Overdose: Unintentional administration of a quantity of the study intervention 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 intervention or 
comparator as applicable. This also takes into account cumulative effects due to overdose.
Underdose: Unintentional administration of a quantity of the study intervention 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 
RLM at a dose less than 10 μg BID, a dose of 10 μg once daily will be considered an underdose.
8.4.
Treatment of Overdose
The sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator must:
1. Contact the MSP immediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention 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.
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8.5.
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6.
Pharmacodynamics
PD parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers
Biomarkers or other assessments are not used in the study.
8.9.
Health Economics
Health economics outcomes will not be captured in this study.
9.
Statistical Considerations
9.1.
Statistical Hypothesis
There is no specific statistical hypothesis in this study.
9.2.
Sample Size Determination
There were no sample size calculations performed for this study.
9.3.
Population for Analyses
The analysis populations will consist of participants as defined in Table 9-1.
Table 9-1
Analysis Populations
Population
Definition
Enrolled
All enrolled participants who sign informed consent
Safety
All participants who received ≥ 1 administration of study intervention
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9.4.
Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the participant 
populations to be included in the analyses. This section is a summary of the planned statistical
analyses:
Methodology
Description
Categorical counts
!
Number of participants in individual categories
o
Participants with ≥ 1 qualifying event counted once per individual category
Categorical 
descriptives
!
Number and percentage of participants in individual categories
o
Participants with ≥ 1 qualifying event counted once per individual category
!
N1 if percentage denominator ≠ number of participants in the population (standard 
percentage denominator)
o
N1 = participants with nonmissing baseline value
Continuous 
descriptives
!
N1, mean, SD, median, minimum, maximum
!
N1 = participants with nonmissing value
Event descriptives
!
Number and percentage of events in individual categories
o Events counted individually for each instance
!
Percentage denominator = total number of events
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
Shift analyses
!
Number and percentage of participants in individual baseline and postbaseline 
categories
!
Percentage denominator = number of participants in individual baseline categories
!
N1 = participants with nonmissing values at both baseline and the specified 
postbaseline analysis visit
9.4.1.
Safety Analyses
The safety analysis will be performed using the safety population and will be fully defined in the 
SAP. No endpoints were specified for this study. The safety parameters will include AEs, vital 
signs, clinical laboratory tests (hematology, clinical chemistry including HbA1c, urinalysis), and 
ECG values reported as clinically significant AEs.
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9.4.1.1.
Adverse Events
An AE will be considered a TEAE if:
!
The AE began on or after the date of the first dose of study intervention; or
!
The AE was present before the date of the first dose of study intervention, but increased in 
severity or became serious on or after the date of the first dose of study intervention
An AE that occurs more than 30 days after the last dose of study intervention will not be counted 
as a TEAE.
An AE will be considered a TESAE if it is a TEAE that additionally meets any SAE criteria.
The number and percentage of participants reporting TEAEs will be tabulated by the MedDRA 
SOC and preferred term, and by SOC, preferred term, and severity (MedDRA version 21.0 or 
newer).
The number and percentage of participants reporting treatment-related TEAEs will be tabulated 
by SOC 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 most severe occurrence for the 
summarizations by severity.
Summary tables will be provided for participants with TESAEs and participants with TEAEs
leading to discontinuation. Listings of all AEs, SAEs, and AEs leading to discontinuation by 
participant will be presented.
The definitions of an AE and SAE can be found in Appendix 3.
9.4.1.2.
Clinical Laboratory Assessments
Descriptive statistics for clinical laboratory values (in SI units) at baseline and changes from 
baseline at each assessment will be presented for each clinical laboratory assessment.
The criteria for PCS laboratory values will be detailed in the SAP. The number and percentage of 
participants who have PCS postbaseline clinical laboratory values will be tabulated at each 
assessment. The percentages will be calculated relative to the number of participants who have 
available non-PCS baseline values and at least 1 postbaseline assessment. The numerator will be 
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the total number of participants with at least 1 PCS postbaseline value. A supportive listing of 
participants with PCS postbaseline values will be provided for the safety population. 
Shift tables from baseline to end of study for clinical laboratory parameters will be presented.
Study-specific assessments (eg, HbA1c) will be summarized as part of the overall clinical 
laboratory assessments.
9.4.1.3.
Vital Signs
Descriptive statistics for vital signs (systolic and diastolic BP, pulse rate, weight, respiration rate, 
and temperature) at baseline (screening) and changes from baseline at each assessment will be 
presented.
Vital sign values will be considered to be PCS if they meet both the observed-value criteria and 
the change-from-baseline-value criteria that will be detailed in the SAP. The number and 
percentage of participants who have PCS postbaseline vital sign values will be tabulated for each 
assessment. The percentages will be calculated relative to the number of participants who have 
available non-PCS baseline values and at least 1 postbaseline assessment. The numerator will be 
the total number of participants with at least 1 PCS postbaseline value. A supportive listing of 
participants with PCS postbaseline values will be provided for the safety population.
Shift tables from baseline to end of study for vital signs will be presented.
9.4.1.4.
Electrocardiogram
No specific analyses for ECGs are planned. Clinically significant findings related to ECG results 
will be recorded as AEs and will be included as part of the AE analyses.
9.5.
Interim Analyses
No interim analysis is planned.
9.6.
Data Monitoring Committee
A Data Monitoring Committee was not used for this study.
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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
o
Applicable ICH/ISO GCP guidelines
o
Applicable laws and regulations
!
The protocol, protocol amendments, ICF, investigator’s brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.
!
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
!
The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
o
Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, 
the IRB/IEC, and European regulation 536/2014 for clinical studies (if applicable)
10.1.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
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certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the study and for 1 year after 
completion of the study.
10.1.3.
Informed Consent Process
!
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
!
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, HIPAA requirements, where applicable, and 
the IRB/IEC or study center. 
!
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.
!
Written documentation must be obtained in accordance with the relevant country and local 
privacy requirements, where applicable (eg, Written Authorization for Use and Release of 
Health and Research Study Information [US sites] and written Data protection Consent 
[European sites]).
!
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
!
A copy of the ICF(s) must be provided to the participant. 
Additionally, in accordance with relevant country requirements, written informed consent is to 
be obtained from each participant prior to enrollment into the study. The informed consent form 
includes explanation of the following:
1. That the study involves research
2. The objectives of the study
3. The study procedures
4. The expected duration of the participant’s participation in the study
5. The approximate number of participants involved in the study
6. The reasonably foreseeable risks or inconveniences to the participant
7. The alternative procedures or courses of treatments that may be available to the participant, 
and their important potential benefits and risks
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8. The compensation and/or treatment available to the participant in the event of study-related 
injury
9. That the participant’s participation in the study is voluntary and that the participant may 
refuse to participate or withdraw from the study at any time, without penalty or loss of 
benefits to which the participant is otherwise entitled
10. That the participant will be informed in a timely manner if information becomes available 
that may be relevant to the participant’s willingness to continue participation in the study
11. The foreseeable circumstances and/or reason under which the participant’s participation in 
the study may be terminated
12. That the monitors, auditors, the IRB, and the regulatory authorities may provide direct 
access to the participant’s original medical records. In such cases, the confidentiality of the
participant should be protected, and by signing and sealing an informed consent form, the
participant is authorizing such access.
13. If the results of the study are published, the participant’s identity will remain confidential.
14. The anticipated expenses, if any, to the participant for participating in the study
15. The anticipated prorated payment, if any, to the participant for participating in the study
16. The name, title, and address of the investigator to contact
17. The person(s) to contact for further information regarding the clinical study and the rights of 
participants, and whom to contact in the event of study-related injury
18. The type of the IRB engaged in the assessment and deliberation about the acceptability of 
the study, items subject to the assessment of each IRB, and other IRB-related items relating 
to the study
19. The participant’s responsibilities
10.1.4.
Data Protection
!
Participants will be assigned a unique identifier. Any participant records or datasets that 
are transferred to the sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
!
The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 
!
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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10.1.5.
Posting Clinical Study Data
All data generated in this study are the property of the sponsor. An integrated clinical and 
statistical report will be prepared at the completion of the study.
10.1.6.
Data Quality Assurance
!
All participant data relating to the study will be recorded on eCRFs unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
!
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
!
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
!
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator as stated in the clinical trial agreement. No records 
may be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification to 
the sponsor. 
10.1.7.
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.
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!
Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available.
10.1.8.
Study and Site Closure
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development
10.1.9.
Publication Policy
!
Allergan as the sponsor has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between the investigator or multiple 
investigators and sites and Allergan personnel. Authorship will be established prior to the 
writing of the manuscript. As this study involves multiple centers, no individual 
publications will be allowed prior to completion of the final report of the multicenter 
study except as agreed with Allergan.
!
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
the case of a multicenter study, a coordinating investigator will be designated by mutual 
agreement.
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!
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.
!
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
10.1.10.
Compliance with Protocol
The investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review participant and 
study intervention accountability records for compliance with the protocol. Protocol deviations 
will be discussed with the investigator upon identification. Significant protocol deviations will be 
reported to the IRB/IEC according to the IRB/IEC’s reporting requirements.
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10.3.
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.3.1.
Definition of AE
AE Definition
!
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.
!
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated 
with the use of study intervention.
For devices, disease signs and symptoms that existed prior to the study intervention are 
not considered AEs.
AE of Special Interest (AESI)
An adverse event of special interest (serious or nonserious) is one of scientific and 
medical concern specific to the sponsor’s study drug/device or program, which warrants 
ongoing monitoring and rapid communication by the investigator to the sponsor. Such an 
event might warrant further investigation in order to characterize and understand it.
The following AESI(s) have been identified for the study intervention(s) in this protocol 
(see Section 8.3.7): 
1. Hy’s law cases
2. Inadequate control of diabetes: hyperglycemia and hypoglycemia
Serious AESIs must be reported to the sponsor within 24 hours via the SAE form. 
Nonserious AESIs do not require submission on an SAE form; should be recorded on the 
appropriate page of the eCRF. 
Potential Hy’s Law Cases
For potential Hy's law cases, refer to Appendix 9.
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Events Meeting the AE Definition
!
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease); for example:
o
The test result is associated with accompanying symptoms, and/or
o
The test result requires additional diagnostic testing or medical/surgical 
intervention, and/or
o
The test result leads to a change in study dosing (outside of any protocol-specified 
dose adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy, and/or
o
The test result is considered to be an AE by the investigator or sponsor.
!
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition
!
New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study
!
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction
!
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE or SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
!
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AEs or SAEs if they fulfil the definition of an AE or SAE. Also, lack of 
efficacy or failure of expected pharmacological action also constitutes an AE or 
SAE.
Events NOT Meeting the AE Definition 
!
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.
!
The disease/disorder being studied or expected progression, signs, or symptoms 
(clearly defined) of the disease/disorder being studied, unless more severe than 
expected for the participant’s condition.
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!
The following events are considered to be manifestations of DG, and they will not be 
reported as AEs or SAEs: nausea, abdominal pain, upper abdominal pain, vomiting, 
postprandial fullness, bloating, and early satiety.
!
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE
!
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)
!
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen
10.3.2.
Definition of SAE
If an event is not an AE per the definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death due 
to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life threatening
The term life threatening in the definition of serious refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or intervention that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the AE is 
to be considered serious.
Hospitalization for elective intervention of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
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d.
Results in persistent disability/incapacity
!
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
!
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:
!
Medical or scientific judgment is to be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events are usually considered 
serious.
Examples of such events include invasive or malignant cancers, intensive 
intervention in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
10.3.3.
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording
!
When an AE or SAE occurs, it is the responsibility of the investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.
!
The investigator will then record all relevant AE or SAE information in the eCRF.
!
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the sponsor in lieu of completion of AE or SAE eCRF page.
!
There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to the sponsor.
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!
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
MILD
A type of AE that is usually transient and may require only minimal treatment 
or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
MODERATE
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant.
SEVERE
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention.
An event is defined as serious when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality
!
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE.
!
A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.
!
The investigator will use clinical judgment to determine the relationship.
!
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.
!
The investigator will also consult the investigator’s brochure and/or product 
information, for marketed products, in his/her assessment.
!
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
!
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the sponsor.
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!
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
!
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs
!
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals
!
If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide the sponsor with a copy of any post-mortem 
findings including histopathology
!
New or updated information will be recorded in the originally completed eCRF
!
The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information
10.3.4.
Reporting of SAEs
SAE Reporting to Sponsor or Designee Within 24 Hours
!
Email is the preferred method to transmit SAE information. 
 
!
Facsimile transmission of the SAE information is also acceptable. 
 
!
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE form, sent by overnight mail or 
courier service.
!
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE/SADE form within the designated reporting time frames.
!
Contacts for SAE reporting can be found on the protocol title page.
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10.4.
Appendix 4: Abbreviations
Term/Abbreviation
Definition
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ALP
alkaline phosphatase
AST
aspartate aminotransferase
AT
aminotransferases 
BID
twice daily
BP
blood pressure
CDISC
Clinical Data Interchange Standards Consortium
CFR
Code of Federal Regulations
CPT
common protocol template
CRF
case report form
DG
diabetic gastroparesis
DILI
drug-induced liver injury
DGSSD
diabetic gastroparesis symptom severity diary
DM
diabetes mellitus
ECG
electrocardiogram
eCRF
electronic case report form
FDA
Food and Drug Administration
FPFV
first participant first visit
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GE
gastric emptying
GERD
gastroesophageal reflux disease
GHS1α
Growth Hormone Secretagogue 1α
GP
gastroparesis
HbA1c
hemoglobin A1c
HIPAA
Health Insurance Portability and Accountability Act
HR
heart rate
HRT
hormonal replacement therapy
IC
informed consent
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
independent ethics committee
INR
international normalized ratio
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Term/Abbreviation
Definition
IRB
Institutional Review Board
ISO
International Organization for Standardization
MedDRA
Medical Dictionary for Regulatory Activities
MSP
Medical Safety Physician
NASH
nonalcoholic steatohepatitis
NCI
National Cancer Institute
PCS
potentially clinically significant
PD
pharmacodynamic
PK
pharmacokinetic
Etc.
QT interval corrected for heart rate 
QT interval
Time between Q wave and T wave in heart’s electrical cycle
RLM
relamorelin
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SD
standard deviation
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reactions
SOC
system organ class
TBL
total bilirubin
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
T1DM
Type 1 diabetes mellitus
T2DM
Type 2 diabetes mellitus
ULN
upper limits of normal
US
United States
WOCBP
Woman/women of childbearing potential
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10.5.
Appendix 5: Standard Discontinuation Criteria
CDISC 
Submission 
Value
CDISC Definition
Adverse event
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. For further information, see the ICH Guideline for Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting (modified from ICH E2A)
Synonyms: side effect, adverse experience. See also serious adverse event, serious adverse 
experience. (CDISC glossary)
Completed
To possess every necessary or normal part or component or step; having come or been 
brought to a conclusion (NCI)
Death
The absence of life or state of being dead (NCI)
Lost to follow-up
The loss or lack of continuation of a subject to follow-up
Other
Different than the one(s) previously specified or mentioned (NCI)
Physician 
decision
A position, opinion or judgment reached after consideration by a physician with reference to 
subject (NCI)
Pregnancy
Pregnancy is the state or condition of having a developing embryo or fetus in the body 
(uterus), after union of an ovum and spermatozoon, during the period from conception to 
birth. (NCI)
Protocol 
deviation
An event or decision that stands in contrast to the guidelines set out by the protocol (NCI)
Screen failure
The potential subject who does not meet one or more criteria required for participation in a 
trial
Site terminated 
by sponsor
An indication that a clinical study was stopped at a particular site by its sponsor (NCI)
Study terminated 
by sponsor
An indication that a clinical study was stopped by its sponsor (NCI)
Withdrawal by 
subject
An indication that a study participant has removed itself from the study (NCI)
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10.6.
Appendix 6: Study Tabular Summary
Parameter Group
Parameter
Value
Trial information
Trial Title
Open-label Extension Study of Relamorelin 
for the Treatment of Diabetic Gastroparesis
Clinical Study Sponsor
Allergan
Trial Phase Classification
Phase 3 Trial
Trial Indication
DG
Trial Indication Type
Treatment
Trial Type
Safety
Trial Length
Until the product becomes commercially 
available or the sponsor terminates 
development
Planned Country of Investigational Sites
multiple
Planned Number of Subjects
~1000
FDA-Regulated Device Study
No
FDA-Regulated Drug Study
Yes
Pediatric Study
No
Subject 
information
Diagnosis Group
NA 
Healthy Subject Indicator
No
Planned Minimum Age of Subjects
18 years
Planned Maximum Age of Subjects
NA
Sex of Participants
Both
Stable Disease Minimum Duration
3 months
Treatments
Investigational Therapy or Treatment
RLM
Intervention Type
Drug
Pharmacological Class of Invest. Therapy
Synthetic ghrelin analogue
Dose per Administration
10
Dose Units
μg
Dosing Frequency
BID
Route of Administration
SC
Current Therapy or Treatment
RLM
Added on to Existing Treatments
No
Control Type
N/A
Comparative Treatment Name
N/A
Trial design
Study Type
Interventional
Intervention Model
Open-label
Planned Number of Arms
1
Trial is Randomized
No
Randomization Quotient
N/A
Trial Blinding Schema
N/A
Stratification Factor
N/A
Adaptive Design
No
Study Stop Rules
No
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10.7.
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions
Women of Child Bearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Women in the following categories are not considered WOCBP:
1. Premenarchal 
2. Premenopausal female with 1 of the following:
!
Documented hysterectomy
!
Documented bilateral salpingectomy
!
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female
!
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient. 
!
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.8.
Appendix 8: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.8.1.
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 6.1 for the list of sponsor medical 
devices).
Medical Device Incident Definition
!
A medical device incident is any malfunction or deterioration in the characteristics and/or 
performance of a device as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
participant/user/other person or to a serious deterioration in his/her state of health.
!
Not all incidents lead to death or serious deterioration in health. The nonoccurrence of such a 
result might have been due to other fortunate circumstances or to the intervention of health 
care personnel.
It is sufficient that:
!
An incident associated with a device happened.
AND
!
The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:
!
Life-threatening illness
!
Permanent impairment of body function or permanent damage to body structure
!
Condition necessitating medical or surgical intervention to prevent one of the above 
!
Fetal distress, fetal death, or any congenital abnormality or birth defects

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Examples of Incidents
!
A participant, user, caregiver, or healthcare professional is injured as a result of a medical 
device failure or its misuse.
!
A participant’s study intervention is interrupted or compromised by a medical device failure.
!
A misdiagnosis due to medical device failure leads to inappropriate intervention.
!
A participant’s health deteriorates due to medical device failure.
10.8.2.
Documenting Medical Device Incidents
Medical Device Incident Documenting
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10.9.
Appendix 9: Liver Safety: Suggested Actions and Follow-up 
Assessments 
Close monitoring should be initiated for the following participants:
!
Participants with normal baseline serum aminotransferases (AT) who develop an increase 
of serum AT ≥3 × ULN
!
Participants with elevated baseline AT who develop an increase of serum AT > 2 × the 
baseline value
The participant should return to the study site and be evaluated for potential drug-induced liver 
injury (DILI) as soon as possible, preferably within 48 to 72 hours from the time the investigator 
becomes aware of the abnormal results. Evaluation should typically include repeat testing of all 
4 of the usual serum biochemical measures (ALT, AST, ALP, and TBL) to confirm the 
abnormalities and to determine if they are increasing or decreasing. 
If it is difficult for the participant to return to the study site promptly, the participant should be 
retested locally, but normal laboratory ranges should be recorded, results should be made 
available to sponsor’s study physician and the investigator immediately, and the data should be 
included in the eCRF. If repeat testing within this time frame is not possible, the study 
intervention should be discontinued.
It is critical to initiate close monitoring immediately upon detection and confirmation of signals 
of potential DILI as early as possible and not to wait until the next scheduled visit or monitoring 
interval. Close monitoring of the participant should be initiated in conjunction with the sponsor 
and consideration given to the following:
!
Obtain a more detailed history of symptoms and prior or concurrent diseases. 
!
Obtain a history of concomitant drug use, including nonprescription medications, herbal 
products and dietary supplements, alcohol and recreational drug use, and special diets. 
!
Obtain a history of exposure to environmental chemical agents. 
!
Initiation of appropriate evaluations including applicable laboratory tests (eg, direct 
bilirubin, INR), physical assessments, and other assessments (eg, imaging)
o Rule out other potential causes of biochemical abnormalities, eg, acute viral hepatitis 
types A, B, C, D, and E; autoimmune or alcoholic hepatitis; NASH; hypoxic/ischemic 
hepatopathy; and biliary tract disease. 
!
Consider gastroenterology or hepatology consultations.
If any of the following criteria are met, discontinuation of study intervention should be 
considered (if indicated, prior to receipt of confirming retest biochemistry laboratory test results) 
and the sponsor notified of the discontinuation:
!
ALT or AST ≥ 3 × ULN and the participant is symptomatic with the appearance of 
fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia (> 5%)
!
ALT or AST ≥ 3 × ULN and total bilirubin > 2 × ULN or INR > 1.5 
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!
ALT or AST ≥ 5 × ULN for more than 2 weeks
!
ALT or AST ≥ 8 × ULN
If the study intervention is discontinued, the participant may be re-challenged with study 
intervention only after consultation with the Allergan MSP. All participants showing potential 
DILI should be followed until all abnormalities return to normal or to the baseline state.
Reporting of Potential Hy’s Law Cases
Potential Hy’s law cases are defined by biochemical test results of hepatocellular injury and 
impaired hepatic function. They are considered Adverse Events of Special Interest (AESIs) and 
should be evaluated and followed further (ie, close monitoring initiated) to determine whether 
these laboratory abnormalities are indicative of DILI. As indicated above, discontinuation of 
study intervention should also be considered. Criteria that identify a potential Hy’s law case are 
as follows:
!
ALT or AST ≥ 3 × ULN AND
!
Total bilirubin ≥ 2 × ULN AND
!
Alkaline phosphatase < 2 × ULN
Sites must report every participant who meets the Hy’s law criteria if this occurs within the time 
the participant signs the ICF until 30 days after the last dose of study intervention.
A laboratory alert for a potential DILI case will be sent immediately to the sponsor and 
investigators when the above criteria have been met, even if no clinical symptoms have been 
experienced. 
 
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11.
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