The following changes were implemented with Amendment 1: -Added Screening and Run-in Periods to the protocol to allow participants to enter the study as de novo participants -Supplemented and revised the study schematic -Revised and supplemented the objectives and endpoints -Revised the number of participants and the description of the study population -Updated the Schedule of Activities (SoA) to add columns for Screening and Run-in, renumbered visits, and updated the footnotes -Deleted endpoint definitions -Revised the clinical hypotheses to present 2 new hypotheses in place of the original 4 hypotheses -Revised the number of participants -Updated the inclusion and exclusion criteria in to allow for participants who enrolled directly into RLM-MD-04; added 2 additional exclusion criteria -Updated the rational for the inclusion and exclusion criteria -Updated treatments administered -Updated treatment compliance -Updated concomitant therapy to alert the investigator that concomitant therapies should be held stable during the study, and to insert an exception to the prohibition for opioid use -Updated rescue medicine -Updated treatment after the end of the study -Updated temporary discontinuation -Updated study assessments and procedures -Updated primary efficacy assessments -Deleted secondary efficacy assessments -Added 2 new sections to include participants Global Impression of Status (PGIS-DG), and Patient Global Impression of Change (PGIC-DG).

-Added treatment continuation -Revised time period and frequency for collecting adverse event (AE) and serious adverse event (SAE) information -Updated major adverse cardiovascular events -Updated treatment of overdose -Updated physical examination -Updated self-monitoring of blood glucose -added resource utilization assessment -Updated analysis populations -Updated statistical analyses -Updated efficacy analyses -Updated key endpoints -Updated missing data -Updated other screening tests -Updated tabular summary.

The following changes were implemented with Amendment 2: -Updated SoA footnote (b) to indicate the early termination visit was performed as soon as possible after the decision has been made -Updated SoA (f) footnote to include evaluation of injection sites -Updated SoA footnote (j) to clarify the details of urine drug screen results -Updated SoA footnote (l) to indicate pregnancy testing can be performed if required by local regulations -Updated the SoA to add a new footnote (u) to inspect injection sites for clinically significant reactions -Revised inclusion criterion to remove the treatment requirement “for at least 3 months” for participants being treated with medications for diabetes mellitus type I (T1DM) or diabetes mellitus type II (T2DM) -Revised inclusion criterion to remove the upper limit for body mass index (BMI) -Revised exclusion criterion (History of intestinal malabsorption) for clarification that celiac disease even if well-controlled on gluten-free diet is exclusionary, and to add history of non-celiac gluten sensitivity as exclusionary -Revised exclusion criterion to remove functional dyspepsia -Deleted exclusion criterion which addresses anemia; in its place added exclusion criterion for gastric or duodenal ulcer within 3 months of screening -Revised exclusion criterion to reduce history of malignancy from 5 to 3 years -Revised exclusion criterion to shorten the exclusion period for promotility agents from 2 weeks to 10 days -Revised exclusion criterion which addresses positive drug screen results -Revised exclusion criterion to extend the exclusion for use of glucagon-like peptide-1 (GLP-1) agonists to 6 weeks, and remove pramlintide -Revised exclusion criterion to remove the allowance for gluten-free crackers -Added exclusion criterion for functional dyspepsia diagnosed before the diagnosis of diabetes mellitus.

-Revised screen failures to disallow rescreening after greater than 6 months -Shortened the wash-out period for pro-motility agents, anticholinergics, anti-emetics, amylin analogue, and opioids from 2 weeks to 10 days; to extend the exclusion for use of GLP-1 agonists from 2 to 6 weeks prior to the start of the Run-in Period -Revised withdrawal from the study to indicate the early termination visit was performed as soon as possible after the decision to discontinue was made -Amended study assessments and procedures to increase the maximum amount of blood collected from 73.0 mL to 74.5 mL -Revised the time period for AE/SAE Collection to include “until 30 days after” the final visit -Amended the major adverse cardiovascular events (MACE) text for clarity and to describe the planned adjudication process -Amended physical examinations to add text about injection site inspection -Added anti-relamorelin antibodies test to other laboratory assessments -Revised the contraception guidance and added recommendations for acceptable birth control methods.

The following changes were implemented with Amendment 3: -Replaced “Potential Hy’s Law” with “Hy’s Law” -Removed responder endpoints from list of key endpoints -Updated key objectives -Addition of other objectives and corresponding “Other Endpoints’’ -Schematic updated to show screening starting at Week -6 instead of Week -4 -Increased number of screening participants from 4000 to 5000 -Added requirements for “de novo” participants to have had a history of nausea and/or at most a single episode of vomiting in 2 weeks prior to screening added at screening Visit (Visit -2) -Deleted requirement for BMI -Increased number of sites from 400 to 700 -Deleted criterion for BMI > 18.5 kg/m2 -Beginning of Screening Period changed from Day -28 to Day -42; changed from “Up to 14 Days” to “Up to 28 Days” -Statement added to footnote (a) that results from assessments done at screening that might result in exclusion from the study are to be obtained prior to the endoscopy if done at the start of the Run-in Period -Added electrocardiogram (ECG) assessment at Visit 2 -Modified footnote (j) referencing to specify certain prescribed drugs (ie, barbiturates, benzodiazepines, amphetamines, but not opioids and cannabinoids) should not be exclusionary -Footnote “k” added for fasting glucose to be serum for all visits except Visits 4 and 6 (plasma) -Modified hypotheses -Changed requirement for delayed gastric emptying breath test (GEBT) from occurring at Screening to occurring during the Run-in Period -Modified inclusion criteria to add option to use upper GI series with contrast to document absence of obstructing lesion; revised time of performance from some time prior to Screening to some time prior to the Run-in Period -Section added for 2 new exclusion criteria applicable to both sets of participants including specific ECG results, allergy/hypersensitivity to study treatment.

-Amended exclusion criteria to allow a participant with a positive urine drug screen at Screening to continue in the study while confirmatory testing is done on an aliquot of the original sample -Added reference to screen failures -Added exclusion criteria (hypersensitivity to study treatments and their excipients) and (ECG results obtained at baseline that would exclude a participant) -Added option for the sponsor to permit a participant with a positive urine drug screen at Screening to continue in the Screening Period while confirmatory urine drug screen testing by a more specific method is carried on an aliquot of the original sample -Clarified that the first dose of study treatment is to be administered within approximately 30 minutes before the morning meal and the second daily dose is to be administered approximately 30 minutes before the evening meal -Deleted option for investigator to contact sponsor if the participant could not inject study treatment into abdomen -Unblinding procedures modified; requirement of investigator to notify sponsor prior to unblinding modified to encouraging the investigator to notify the sponsor prior to unblinding, but requiring notification within 24 hours after breaking the blind -Sodium-glucose co-transporter-1 (SLGT-1) added to same rules for sodium-glucose co-transporter-2 (SGLT-2), Addition of details to the requirement of prohibiting SGLT-1 and SGLT-2 inhibitors -Amended information regarding SGLT-2 inhibitors as noted above and by adding SLGT-1 to same drug class/treatment as SGLT-2, rearranged rows by washout period, added tramadol as an example of opioid.

-Added washout requirements for de novo participants -pro-motility agents, anticholinergics, anti-emetics, amyline analogue, 5 hydroxy tryptamine 4 (5HT4) agonists, and glucagon-like peptide-1 -Updated description of antiemetics -Added row for 5HT4 agonists -Amended washout period for opioids from “10 days prior to the start of the Run-in Period” to Not applicable since use of opioids is not allowed and referenced exclusion criteria -Specified that the day prior to and day of clinic visits are “during the Treatment Period” -Deleted antihistamines as an example of an anti-emetic drug -Revised to require investigator to contact (i.e., “should contact) sponsor if participant requires anti-emetic more than 1 day/week or once weekly repeatedly instead of making it optional for investigator to contact (i.e., “should consider contacting) -Deleted “non-compliance with study treatment” as a criterion -Additional criteria added for when the investigator should contact the sponsor -Added statement detailing when participants would be reporting their symptoms in the DGSSD -Deleted description on vomiting frequency and how vomiting was calculated -Changed title from “Other Patient-reported Outcomes (PRO) Assessments – Exploratory Endpoints to “Additional Assessments’’ -Added a subsection (i.e., Section 9.1.2.1) for description and calculation of vomiting frequency and renumbered all subsequent subsections accordingly -Specified that medical occurrences that begin before the start of study treatment but after obtaining informed consent was recorded in the AE section of the eCRF and was considered pretreatment AEs (instead of being recorded on the Medical History/Current Medical Conditions section of the eCRF) -Clarified reporting procedures for Hy’s Law cases -Added the phrase “Inadequate Control of Diabetes” to section title -Specified 10 μg twice a day (BID) or 20 μg/day as the maximum recommended dose.

-Deleted statement referencing a dose of greater than 150 μg BID to be considered an overdose -Specified that the mITT Population is a subset of all randomised participants -Replaced Responder analysis with Change from Baseline (CFB) mixed model for repeated measures (MMRM) methodology and description -Deleted CFB ANCOVA methodology and description -Updated to only include CFB to Week 12 in weekly DGSSS and CFB to Week 52 in weekly average DGSSS -Deleted original text in section Section 10.3.2.2 Missing Data and replaced with reference to statistical analysis plan (SAP) -Added statement that data analyses for additional endpoints was specified in the SAP -Deleted language that PRO and HEOR measures was presented separately from CSR -Replaced the “Non-applicable” statement with a description of a DSMB process that was used to review interim safety data -Footnote added for fasting blood glucose to be serum at all visits except for Visits 4 & 6 -Headings added for subsections -Statement added that written documentation was obtained in accordance with relevant country and local privacy requirements -Revised from requirement of investigator retaining records for 15 years after study completion to retaining “as stated in the clinical trial agreement” -Added statement that the results of the study may be published or presented at scientific meetings -Updated procedures for reporting adverse events of special interest (AESIs) -Identified specific AESIs -Specified that DG symptoms were captured in the DGSSS and not the CRF -Moved acceptable methods of contraception from text to table -Deleted footnote “b” regarding hormonal contraception’s susceptible interactions with study intervention -Female participants who become pregnant –Deleted text that an elective termination is an AE or SAE; provided examples and details for abnormal pregnancy outcomes, including genetic abnormalities -Removed criteria for noncompliance -Changed trial length from 52 to 54 weeks.