📚 Part of the GLPI-103 Regulatory Dossier — Reader's Guide. This article shows the live document; edits to the source appear here automatically.

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Clinical Study Protocol — GLPI103-301

Field	Value
Document ID	PROT-301
Version	3.0 (full submission-grade)
Status	Final
Effective Date	2026-06-29
Study No.	GLPI103-301
EudraCT / IND / KR-IND	[MOCK] 2026-0XXXXX-XX / IND 1XXXXX / KR-IND-XXXX
Compound	GLPI-103 (GLP-1 / Apelin [APJ] receptor dual agonist)
CDISC STUDYID	GLPI103
Sponsor	Virtual Biopharma Inc.
Standard(s)	ICH E6(R3) · E8(R1) · E9 / E9(R1) · E2A · E3 · SPIRIT 2013
Confidentiality	Confidential

Eligibility criteria, the Schedule of Activities, treatments, and statistical methods correspond exactly to the executable simulation (src/) and canonical parameters (REF-002), so the protocol, datasets, SAP-301, and CSR-301 are mutually consistent.

Change History

Version	Date	Author	Summary of Change
1.0	2026-06-29	Clinical	Initial synopsis-level protocol
2.0	2026-06-29	Clinical / Biostat / RA	Full protocol (objectives/estimands, population, treatments, SoA, statistics)
3.0	2026-06-29	Clinical / Biostat / RA / PV	Submission-grade expansion — full prose detail across all sections; added dose-modification algorithms, rescue criteria, hypoglycaemia classification, AE/SAE workflows, statistical detail, governance, and appendices

Sponsor Signature Page [MOCK]

By signature below, the sponsor confirms this protocol was prepared in accordance with ICH E6(R3) and applicable regulations. Sponsor Medical Responsible: __________ (Date). Biostatistics Responsible: __________ (Date). The coordinating/principal investigator agrees to conduct the study per this protocol, ICH GCP, and applicable law (investigator agreement page filed per site, TMF-CTA).

Protocol Synopsis

Item	Description
Full Title	A Phase 3, Randomized, Double-Blind, Double-Dummy, Active-Controlled, Parallel-Group, Multicenter Trial Evaluating the Efficacy and Safety of GLPI-103 (Intravenous and Oral) versus Oral Semaglutide in Adults with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin
Phase	3 (confirmatory, pivotal)
Design	Randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter
Indication	Type 2 diabetes mellitus inadequately controlled on stable metformin
Primary objective	Demonstrate superiority of GLPI-103 (IV and Oral) versus oral semaglutide on change from baseline (CFB) in HbA1c at Week 52
Treatment arms (1:1:1)	A: GLPI-103 IV (1→2→4 mg once weekly) + oral placebo · B: GLPI-103 Oral (2→4→8 mg once daily) + IV placebo · C: oral semaglutide (3→7→14 mg once daily) + IV placebo
Planned sample size	≈900 randomized (≈300/arm); 90% power, two-sided α=0.05, to detect Δ=0.4% HbA1c (assumed SD≈1.1%); actual randomized 900 (REF-002)
Study duration / per subject	~58 weeks: 2-week screening + 52-week double-blind treatment + 4-week safety follow-up
Primary endpoint	CFB in HbA1c (%) at Week 52
Key secondary endpoints	CFB in body weight; proportion HbA1c <7.0%; proportion ≥10% weight loss (all at Week 52)
Stratification factors	Baseline HbA1c (<8.5% vs ≥8.5%), BMI (<30 vs ≥30 kg/m²), Region
Primary analysis	ANCOVA on the Full Analysis Set; fixed-sequence multiplicity control (SAP-301)

Abbreviations & Definitions

AE adverse event · AESI adverse event of special interest · ALT/AST alanine/aspartate aminotransferase · ANCOVA analysis of covariance · APJ apelin receptor · BMI body mass index · CFB change from baseline · CI confidence interval · CRF case report form · CSR clinical study report · DBP/SBP diastolic/systolic blood pressure · DSMB data safety monitoring board · ECG electrocardiogram · eCRF electronic CRF · eGFR estimated glomerular filtration rate · EOT end of treatment · FAS full analysis set · FPG fasting plasma glucose · GCP good clinical practice · GLP-1 glucagon-like peptide-1 · HbA1c glycated haemoglobin · ICE intercurrent event · ICF informed consent form · IMP investigational medicinal product · IRB/IEC institutional review board / independent ethics committee · IWRS interactive web response system · LS least squares · MedDRA Medical Dictionary for Regulatory Activities · MMRM mixed model for repeated measures · MTC medullary thyroid carcinoma · NOAEL no-observed-adverse-effect level · OAD oral antidiabetic drug · PD/PK pharmacodynamics/pharmacokinetics · PPS per-protocol set · QD/QW once daily/once weekly · SAE serious adverse event · SAP statistical analysis plan · SoA schedule of activities · SUSAR suspected unexpected serious adverse reaction · T2DM type 2 diabetes mellitus · TEAE treatment-emergent adverse event · ULN upper limit of normal · WOCBP woman of childbearing potential.

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1. Introduction & Background

1.1 Disease Background and Burden

Type 2 diabetes mellitus (T2DM) is a chronic, progressive metabolic disease characterized by insulin resistance and progressive β-cell dysfunction, leading to chronic hyperglycaemia and long-term microvascular (retinopathy, nephropathy, neuropathy) and macrovascular (coronary, cerebrovascular, peripheral arterial, heart failure) complications. Despite a broad therapeutic armamentarium, a substantial proportion of patients do not achieve or maintain the glycaemic target of HbA1c <7.0% recommended by major guidelines, and the majority carry concomitant overweight/obesity and elevated cardiometabolic risk. In the Korean population in particular, T2DM prevalence has risen markedly with ageing and lifestyle transition, and a large fraction of patients on metformin remain inadequately controlled, providing the clinical context and the demographic basis of the planned population (epidemiology summarized in REF-002 and the Clinical Development Plan).

1.2 Therapeutic Class and Unmet Need

Glucagon-like peptide-1 (GLP-1) receptor agonists have transformed T2DM management by combining robust glycaemic control with weight reduction and, for several agents, cardiovascular risk reduction. Nonetheless, residual unmet needs persist: a ceiling on glycaemic and weight efficacy for single-mechanism agents; substantial residual cardiometabolic and heart-failure risk; and gastrointestinal tolerability that constrains titration. Therapies that deliver greater metabolic effect together with cardiometabolic benefit, while maintaining acceptable tolerability, would address an important gap.

1.3 Investigational Product and Mechanism of Action

GLPI-103 is a first-in-class, synthetic peptide dual agonist of the GLP-1 receptor and the apelin (APJ) receptor. Activation of the GLP-1 receptor increases glucose-dependent insulin secretion, suppresses inappropriate glucagon secretion, slows gastric emptying, and reduces appetite and caloric intake. Activation of the APJ receptor is associated with enhanced peripheral and hepatic insulin sensitivity, improved endothelial function and nitric-oxide-mediated vasodilation, positive inotropic and lusitropic myocardial effects, and anti-inflammatory activity. The therapeutic hypothesis is that simultaneous engagement of both pathways produces additive/synergistic improvements in glycaemia and body weight, together with favourable cardiometabolic biomarker changes (e.g., NT-proBNP, hsCRP), beyond what is achievable with GLP-1 receptor agonism alone. The molecular and pharmacological basis is summarized in the Nonclinical Overview (M2.4) and the Investigator's Brochure (IB-001).

1.4 Summary of Nonclinical Experience [MOCK]

The nonclinical program was conducted per ICH M3(R2) and the ICH S-series. In primary pharmacology studies (db/db and diet-induced obese rodent models), GLPI-103 produced dose-dependent reductions in HbA1c and body weight that exceeded those of a GLP-1 receptor-only comparator at matched exposure, with improvements in insulin sensitivity and cardiometabolic biomarkers consistent with APJ engagement (M4-2.1). Safety pharmacology (ICH S7A/S7B) revealed no central nervous system, respiratory, or QT/hERG liability, with only transient, mechanism-related changes in heart rate. Pharmacokinetics demonstrated approximately dose-proportional exposure and a long half-life supporting once-weekly intravenous dosing, with proteolytic catabolism and low drug-interaction potential (M4-2.2). The toxicology package (≤26-week rat and ≤39-week monkey repeat-dose studies, genotoxicity, carcinogenicity, and reproductive/developmental studies) identified only reversible exaggerated-pharmacology effects (reduced food intake and body-weight gain) and injection-site reactions, with adequate exposure margins at the no-observed-adverse-effect levels (M4-2.3). Class-appropriate monitoring for thyroid C-cell effects was incorporated.

1.5 Summary of Clinical Experience [MOCK]

First-in-human single ascending dose (GLPI103-101, N=40, healthy volunteers) and multiple ascending dose (GLPI103-102, N=40, overweight/obese adults with T2DM or prediabetes) studies established acceptable safety and tolerability, characterized human pharmacokinetics consistent with the nonclinical profile, and demonstrated dose-dependent reductions in HbA1c and body weight with engagement of mechanistic biomarkers. The Phase 2 dose-finding study (GLPI103-201, N=240, 24 weeks) established a clear dose–response for HbA1c reduction and informed the doses selected for the present study (IB-001; CSR-101/102/201).

1.6 Rationale for the Present Study

This pivotal Phase 3 study is designed to confirm the efficacy and characterize the safety of GLPI-103 (in both intravenous and oral formulations) relative to a guideline-recommended active comparator (oral semaglutide titrated to 14 mg once daily) in adults with T2DM inadequately controlled on metformin. The superiority design against an established GLP-1 receptor agonist provides a clinically meaningful benchmark; the inclusion of both formulations addresses different patient/clinician preferences and dosing settings.

1.7 Benefit–Risk Assessment

The anticipated benefits—superior glycaemic control, substantial weight reduction, and favourable cardiometabolic effects—are weighed against class-related risks (gastrointestinal adverse events; hypoglycaemia in combination with insulin secretagogues; rare potential risks of pancreatitis and thyroid C-cell neoplasia) and mechanism-related considerations (cardiovascular and heart-rate effects associated with APJ activation). The design mitigates risk through an active comparator, stratified randomization, conservative titration, predefined adverse events of special interest, independent data safety monitoring, and protocol-defined stopping and rescue criteria. The overall benefit–risk supports conduct of the study (M2.5.6).

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2. Objectives and Endpoints

Type	Objective	Endpoint(s)	Estimand reference
Primary	To demonstrate superiority of GLPI-103 IV and GLPI-103 Oral versus oral semaglutide in glycaemic control	CFB in HbA1c (%) at Week 52	§3.1
Key Secondary	To compare body-weight reduction	CFB in body weight (kg) at Week 52	§3.2
Key Secondary	To compare attainment of glycaemic target	Proportion of subjects achieving HbA1c <7.0% at Week 52	§3.2
Key Secondary	To compare clinically meaningful weight loss	Proportion achieving ≥10% body-weight reduction at Week 52	§3.2
Secondary	Fasting glycaemia	CFB in FPG at Week 52	§3.2
Secondary	Cardiometabolic biomarkers	CFB in NT-proBNP and hsCRP at Week 52 [MOCK — not in dataset]	§3.2
Secondary	Blood pressure	CFB in SBP and DBP at Week 52	§3.2
Safety	To characterize safety and tolerability	TEAEs, SAEs, AESIs, hypoglycaemia, clinical laboratory, vital signs, ECG	§10
Exploratory	Mechanistic and lifecycle endpoints	Plasma apelin, IL-6, HOMA-IR, adiponectin, leptin; echocardiographic substudy [MOCK]	§9

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3. Estimands (ICH E9(R1))

3.1 Primary Estimand

Attribute	Specification
Treatment	GLPI-103 IV (or GLPI-103 Oral), each administered on background metformin, versus oral semaglutide on background metformin
Population	Randomized adults with T2DM inadequately controlled on metformin meeting all eligibility criteria (Full Analysis Set)
Variable (endpoint)	Change from baseline in HbA1c (%) at Week 52
Intercurrent events (ICEs) & strategies	(a) Premature discontinuation of randomized treatment → treatment-policy strategy: all on-study HbA1c values are used regardless of adherence, and subjects are followed to Week 52 wherever possible; (b) Initiation of rescue antihyperglycaemic medication → hypothetical strategy: the HbA1c value that would have been observed had rescue not been initiated is targeted (post-rescue values are set to missing and handled by the analysis model); (c) Death → handled as part of the population definition (none expected at this duration)
Population-level summary	Difference in least-squares mean change from baseline between each GLPI-103 arm and the comparator

3.2 Secondary Estimands

Secondary endpoint estimands share the treatment, population, and ICE framework of the primary estimand unless otherwise specified. For responder endpoints (HbA1c <7.0%; ≥10% weight loss), subjects with missing Week-52 status due to discontinuation are treated as non-responders in the primary responder analysis (a composite strategy), with multiple-imputation responder analysis as sensitivity.

3.3 Supplementary / Sensitivity Estimands

A treatment-policy estimand for the rescue ICE (using all observed data including post-rescue) and a trial-product (while-on-treatment) estimand are pre-specified as sensitivity analyses to assess robustness of the primary conclusion to ICE-handling assumptions (SAP-301 §6).

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4. Investigational Plan / Study Design

4.1 Overall Design

This is a Phase 3, randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter study conducted at approximately 17 sites across the Republic of Korea (with provision for additional regions in the global program). Eligible subjects are randomized in a 1:1:1 ratio to one of three treatment arms and treated for 52 weeks under double-blind, double-dummy conditions, followed by a 4-week off-treatment safety follow-up. Total per-subject duration is approximately 58 weeks including the 2-week screening period.

4.2 Double-Dummy Blinding Strategy

Because the three arms employ two different routes of administration (intravenous once weekly and oral once daily), a double-dummy approach is used: every subject receives one active product via one route and matching placebo via the other route, such that all subjects receive both an intravenous administration (active or placebo) and an oral administration (active or placebo) of identical appearance. This preserves blinding of subjects, site personnel, and the sponsor study team across routes. Drug-kit assignment and management are handled by a central IWRS (TMF-RAND).

4.3 Study Schema

        Screening          Randomization (1:1:1, stratified)            Treatment 52 wk                 Follow-up
        (2 weeks)          ┌───────────────────────────────────────────────────────────────────┐        (4 weeks)
  ICF, I/E, labs,  ──────► │ Arm A: GLPI-103 IV 1→2→4 mg QW + matching oral placebo             │ ─────►  Safety FU
  randomization            │ Arm B: GLPI-103 Oral 2→4→8 mg QD + matching IV placebo             │         (Week 56)
  stratifiers              │ Arm C: Oral semaglutide 3→7→14 mg QD + matching IV placebo (control)│
                          └───────────────────────────────────────────────────────────────────┘
   Visit weeks:        Scrn   0    4    8   12   16   24   36   52(primary)    56(FU)

4.4 Scientific Rationale for the Design

• Active comparator: oral semaglutide titrated to 14 mg once daily is a guideline-recommended, approved GLP-1 receptor agonist, providing a clinically meaningful and ethically appropriate comparator (placebo monotherapy would be inappropriate given available efficacious therapy).
• Superiority framework: the program targets demonstrably greater efficacy, consistent with the dual-mechanism hypothesis; a superiority margin of 0.4% HbA1c is both statistically detectable and clinically relevant.
• 52-week duration: captures the durable glycaemic effect and allows characterization of weight, tolerability, and longer-term safety.
• Stratified randomization: baseline HbA1c, BMI, and region are prognostic for the endpoints and are balanced to improve precision and comparability.

4.5 Rationale for Doses and Titration

The maintenance doses (GLPI-103 IV 4 mg once weekly; GLPI-103 Oral 8 mg once daily; semaglutide 14 mg once daily) and the 8-week stepwise titration were selected on the basis of Phase 1 safety/PK and the Phase 2 dose–response, balancing maximal efficacy against gastrointestinal tolerability. The conservative titration (two 4-week steps before maintenance) mitigates early gastrointestinal adverse events.

4.6 End of Study Definition

The end of study is defined as the date of the last visit of the last subject (Week 56 follow-up visit) or the date of the last data point required for primary/secondary/safety analyses, whichever is later.

4.7 Study Committees and Oversight

An independent Data Safety Monitoring Board (DSMB) reviews unblinded safety at predefined milestones (TMF-DSMB). A central laboratory provides all efficacy and safety analytes (TMF-LAB). Randomization and drug supply are managed by a validated IWRS (TMF-RAND). Risk-based monitoring is conducted per the Clinical Monitoring Plan (TMF-CMP).

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5. Study Population

The target population is adults with T2DM inadequately controlled on stable metformin. Eligibility criteria correspond exactly to the executable screening logic (src/randomization/screen_and_enroll.py), ensuring protocol–dataset consistency.

5.1 Inclusion Criteria

A subject must meet all of the following to be eligible:

1. Age 18–75 years (inclusive) at screening. Rationale: adult T2DM population; the upper bound limits confounding by age-related comorbidity while retaining the older population in whom T2DM is prevalent.
2. Documented diagnosis of T2DM with HbA1c 7.0–10.5% (inclusive) at screening (central laboratory). Rationale: inadequate glycaemic control with measurable room for improvement; the upper bound excludes very poorly controlled patients who may require insulin.
3. Body mass index ≥ 25 kg/m². Rationale: overweight/obese T2DM, the population relevant to the weight co-primary/secondary endpoints.
4. Treatment with a stable dose of metformin for ≥ 3 months prior to screening (≥1500 mg/day or the maximum tolerated dose). Rationale: defined, stable background therapy.
5. eGFR ≥ 45 mL/min/1.73 m² (CKD-EPI) at screening. Rationale: renal safety threshold.
6. Willing and able to provide written informed consent and to comply with the protocol (visits, self-administration of oral product, study procedures).

5.2 Exclusion Criteria

A subject is excluded if any of the following apply:

1. ALT or AST > 3 × ULN at screening (ULN = 40 U/L). Rationale: hepatic safety.
2. Type 1 diabetes mellitus, or history of diabetic ketoacidosis or hyperosmolar hyperglycaemic state.
3. History of acute or chronic pancreatitis.
4. Personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
5. Use of any GLP-1 receptor agonist within 90 days prior to screening.
6. Clinically significant cardiovascular disease within 3 months (e.g., acute coronary syndrome, stroke, hospitalization for heart failure), or current symptomatic heart failure (NYHA III–IV).
7. Pregnancy or breastfeeding; WOCBP unwilling to use highly effective contraception.
8. Severe renal (eGFR <45) or hepatic impairment; active malignancy; or any condition that, in the investigator's judgment, would compromise subject safety or data integrity.

5.3 Lifestyle and Contraception Requirements

Subjects maintain their habitual diet and physical activity; substantial changes during the study are discouraged and recorded. WOCBP must use a highly effective contraceptive method from screening through the follow-up visit and undergo pregnancy testing per the SoA.

5.4 Screening, Re-screening, and Screen Failures

Subjects who do not meet eligibility are screen failures; the primary reason is recorded. A subject may be re-screened once if a transient condition (e.g., intercurrent illness affecting laboratory values) has resolved. In the executed dataset, 776 of 1,700 screened subjects were screen failures, predominantly due to HbA1c outside the eligible range (CSR-301 §10).

5.5 Subject Replacement

Randomized subjects who discontinue are not replaced; the sample size accounts for anticipated dropout.

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6. Study Treatments

6.1 Investigational Medicinal Products and Dosing

Arm	Active product	Titration (Weeks)	Maintenance (Weeks 8–52)	Matching placebo
A	GLPI-103 IV, once weekly	1 mg (0–3) → 2 mg (4–7)	4 mg QW	Oral placebo, once daily
B	GLPI-103 Oral, once daily	2 mg (0–3) → 4 mg (4–7)	8 mg QD	IV placebo, once weekly
C	Oral semaglutide, once daily	3 mg (0–3) → 7 mg (4–7)	14 mg QD	IV placebo, once weekly

Background metformin is continued unchanged at the pre-study stable dose throughout the treatment period.

6.2 Preparation and Administration

The intravenous product (active or placebo) is prepared by an unblinded pharmacist per the Pharmacy/IMP Manual (TMF-PHARM) and administered at the site under observation once weekly. The oral product (active or placebo) is dispensed for once-daily self-administration with instructions on timing relative to food and water (per the biopharmaceutic recommendations, M2.7.1). All products of a given route are identical in appearance to maintain the blind.

6.3 Dose Modification and Titration Management

• Planned titration: subjects advance through the two titration steps at 4-week intervals to reach maintenance at Week 8.
• For intolerable gastrointestinal adverse events: the next scheduled step-up may be delayed by up to 4 weeks, or the current dose down-titrated by one level with subsequent attempted re-escalation at the investigator's discretion. Blinding is maintained because IWRS-directed kit changes are applied identically across arms.
• Permanent discontinuation of IMP is required for recurrent intolerance despite dose modification, confirmed acute pancreatitis, suspected medullary thyroid carcinoma, severe hypersensitivity, pregnancy, or any safety concern in the investigator's judgment (§7).

6.4 Randomization, Blinding, and Emergency Unblinding

Randomization is performed centrally by the IWRS using permuted blocks within strata defined by baseline HbA1c (<8.5 vs ≥8.5%), BMI (<30 vs ≥30 kg/m²), and Region (TMF-RAND). Subjects, investigators, site staff, and the sponsor study team remain blinded throughout. Emergency unblinding is available 24/7 via the IWRS for medical management when knowledge of treatment is essential; the event is documented and reported, and the subject typically discontinues IMP but continues study assessments.

6.5 Treatment Compliance and Accountability

Compliance with the oral product is assessed by pill count and IWRS records; intravenous administration is observed and documented at site. Compliance <80% or >120% over an interval is recorded as a potential protocol deviation relevant to the Per-Protocol Set. Drug accountability is maintained and reconciled at monitoring visits (TMF-PHARM).

6.6 Prior and Concomitant Medications

Stable metformin is required. Additional glucose-lowering agents are prohibited during the treatment period except protocol-defined rescue therapy (§6.7). Medications that may confound efficacy or safety are recorded; investigators consult the medical monitor when in doubt.

6.7 Rescue Medication Criteria

Rescue antihyperglycaemic therapy (per local standard of care, excluding GLP-1 receptor agonists) may be initiated when pre-specified hyperglycaemia thresholds are met and confirmed on repeat: e.g., FPG > 15 mmol/L (Weeks 0–12) or > 13.3 mmol/L (after Week 12), or HbA1c > 9.0% after Week 24. Initiation of rescue constitutes an intercurrent event handled per the primary estimand (§3.1). Subjects continue randomized IMP and all assessments where possible.

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7. Discontinuation and Withdrawal

7.1 Discontinuation of Study Treatment

Reasons include adverse event/intolerance, confirmed/suspected AESI requiring discontinuation (pancreatitis, MTC), pregnancy, subject decision, or investigator decision. Subjects who discontinue IMP are strongly encouraged to remain in the study for endpoint assessment through Week 52 (consistent with the treatment-policy estimand).

7.2 Withdrawal from the Study

A subject may withdraw consent at any time without penalty. Lost-to-follow-up is declared only after documented attempts to contact (e.g., ≥3 calls and a registered letter). Reasons are recorded on the disposition CRF.

7.3 Study Stopping Rules

The sponsor, on DSMB recommendation, may pause or stop the study for unacceptable safety (e.g., a cluster of serious pancreatitis, an unfavourable cardiovascular signal, or a severe hypoglycaemia imbalance). Predefined considerations and any interim statistical boundaries are described in the DSMB Charter (TMF-DSMB) and SAP-301.

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8. Schedule of Activities (SoA)

Visit weeks correspond to the simulated visit schedule (config visits.schedule); the permitted visit window is ±7 days. "X" indicates the assessment is performed at that visit.

Assessment	Scrn	W0	W4	W8	W12	W16	W24	W36	W52	W56 (FU)
Informed consent	X
Eligibility (I/E) review	X
Demographics / medical history	X
Subject characteristics (SC)	X
Randomization (IWRS)		X
Study drug administration		X	X	X	X	X	X	X	X
HbA1c (central)	X	X	X	X	X	X	X	X	X	X
Fasting plasma glucose	X	X		X		X	X	X	X	X
Body weight / BMI	X	X	X	X	X	X	X	X	X	X
Vital signs (SBP/DBP/HR)	X	X	X	X	X	X	X	X	X	X
Safety labs (ALT/AST/eGFR; haematology)	X	X		X		X	X	X	X	X
NT-proBNP / hsCRP		X			X		X		X
Exploratory biomarkers		X					X		X
Physical examination	X	X					X		X	X
12-lead ECG	X						X		X
Pregnancy test (WOCBP)	X	X					X		X	X
Concomitant medication review	X	X	X	X	X	X	X	X	X	X
Adverse-event assessment	X	X	X	X	X	X	X	X	X	X
IMP accountability / compliance			X	X	X	X	X	X	X

Footnotes: fasting required for FPG and lipids; HbA1c is the primary endpoint analyte (central lab); the Week-52 visit is the primary endpoint timepoint; unscheduled visits may be performed for safety as needed.

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9. Study Assessments and Procedures

9.1 Efficacy Assessments

• HbA1c (primary): measured at the central laboratory (NGSP-aligned) at every scheduled visit; the Week-52 value is the primary endpoint.
• Fasting plasma glucose: central laboratory, fasting.
• Body weight and BMI: standardized measurement (calibrated scale, light clothing, no shoes).
• Responder endpoints: derived (HbA1c <7.0%; ≥10% body-weight reduction at Week 52).
• Cardiometabolic biomarkers: NT-proBNP and hsCRP at the indicated visits, supporting the APJ mechanistic hypothesis [MOCK — not in dataset].

9.2 Safety Assessments

• Adverse events and concomitant medications: continuously, by non-leading questioning and review.
• Clinical laboratory: haematology, chemistry (including hepatic ALT/AST and renal eGFR), urinalysis; central laboratory with alert/critical-value flagging (TMF-LAB).
• Vital signs (including heart rate): standardized measurement after ≥5 minutes seated rest; heart rate monitored given the APJ mechanism.
• 12-lead ECG: at screening, Week 24, and Week 52 [MOCK].
• Physical examination and pregnancy testing per the SoA.

9.3 Pharmacokinetic / Pharmacodynamic and Exploratory Assessments

Sparse PK sampling supports population-PK characterization where applicable. Exploratory mechanistic biomarkers (plasma apelin, IL-6, HOMA-IR, adiponectin, leptin) and an echocardiographic substudy at selected sites support the cardiometabolic hypothesis [MOCK].

9.4 Appropriateness of Measurements

HbA1c is the established, regulatory-accepted primary glycaemic endpoint; central-laboratory measurement minimizes inter-site variability. All assessments are standard for Phase 3 T2DM trials.

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10. Safety Reporting and Pharmacovigilance

10.1 Definitions

An adverse event is any untoward medical occurrence in a subject administered a study treatment, whether or not causally related. A serious adverse event (SAE) meets one or more of: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or is an important medical event (medical judgment). A treatment-emergent adverse event (TEAE) is an AE with onset on or after the first dose of study treatment. Severity is graded mild / moderate / severe; causality is assessed as related / not related to study treatment.

10.2 Adverse Events of Special Interest (AESI)

Based on the mechanism and class, the following are AESIs subject to enhanced surveillance and targeted follow-up:

• Gastrointestinal events (nausea, vomiting, diarrhoea) — managed by titration; severe/persistent events followed.
• Acute pancreatitis — discontinue IMP if suspected; confirm with lipase/amylase and imaging; adjudicate.
• Thyroid C-cell neoplasia / MTC — calcitonin/imaging follow-up of relevant signals; class boxed-warning consideration.
• Hypoglycaemia — classified per international consensus (Level 1: glucose <3.9 mmol/L; Level 2: <3.0 mmol/L; Level 3: severe event requiring assistance); episodes recorded with glucose confirmation.
• Cardiovascular / heart-rate changes (APJ-related) — vital-sign and ECG surveillance.

10.3 Recording, Assessment, and Reporting Workflow

All AEs are recorded on the eCRF with onset/resolution dates, severity, causality, seriousness, action taken, and outcome, and coded to MedDRA. SAEs are reported by the site to the sponsor within 24 hours of awareness; the sponsor performs expedited regulatory reporting of SUSARs (e.g., 7-day for fatal/life-threatening, 15-day for other) per ICH E2A and regional requirements, using the Investigator's Brochure reference safety information (IB-001 §7) for expectedness. Pregnancies and special situations (overdose, medication error, off-label use, occupational exposure) are reported per the Safety Management Plan (TMF-SMP). The DSMB reviews accumulating unblinded safety data (TMF-DSMB).

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11. Statistical Considerations (summary; full detail in SAP-301)

11.1 Sample-Size Determination

Approximately 900 randomized subjects (≈300 per arm) provide ≥90% power, at a two-sided significance level of 0.05, to detect a treatment difference of 0.4% in HbA1c change from baseline versus semaglutide, assuming a common standard deviation of approximately 1.1% and allowing for dropout. The actual number randomized was 900 (REF-002); the implications of under-enrolment for achieved power are discussed in CSR-301.

11.2 Analysis Sets

• Full Analysis Set (FAS): all randomized subjects, analysed according to randomized treatment (intention-to-treat principle); primary efficacy.
• Per-Protocol Set (PPS): FAS subjects without major protocol deviations; supportive.
• Safety Set: all subjects who received ≥1 dose of study treatment, analysed as treated.

11.3 Primary Analysis

The primary endpoint is analysed by analysis of covariance: CHG ~ TRT01A + BASE + STRAT_HBA1C + STRAT_BMI, providing least-squares mean changes by arm and pairwise differences (with 95% confidence intervals and p-values) of each GLPI-103 arm versus semaglutide. A fixed-sequence (hierarchical) testing procedure controls the family-wise type-I error across the primary and key secondary endpoints at the two-sided 0.05 level.

11.4 Secondary, Sensitivity, and Subgroup Analyses

Longitudinal HbA1c is analysed by a mixed model for repeated measures (unstructured covariance with a pre-specified AR(1) fallback). Key secondary endpoints (weight, responders) are analysed by ANCOVA and logistic/CMH methods. Missing data are addressed primarily by the MMRM under a missing-at-random assumption, with pattern-mixture and reference-based multiple-imputation sensitivity analyses and a tipping-point analysis for the primary endpoint. Pre-specified subgroups include baseline HbA1c, BMI, age, and sex.

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12. Data Quality Assurance and Monitoring

Data are captured via a validated electronic data capture system with programmatic edit checks (TMF-DMP). Monitoring is risk-based, with centralized statistical surveillance, remote review, and triggered on-site source-data verification focused on consent, eligibility, the primary endpoint, and serious adverse events, governed by predefined key risk indicators and quality tolerance limits (TMF-CMP). Datasets are standardized to CDISC SDTM and ADaM with a Define-XML and reviewer's guides (DEF-301).

13. Ethics and Regulatory Compliance

The study is conducted in accordance with the ethical principles of the Declaration of Helsinki and ICH E6(R3) Good Clinical Practice. Institutional review board / independent ethics committee approval and applicable regulatory authorization are obtained before study start at each site, and written informed consent (TMF-ICF) is obtained from each subject before any study-specific procedure. Subject confidentiality and personal-data protection are maintained per applicable law.

14. Data Handling and Record Keeping

Source documents and the electronic data capture database constitute the study records; an audit trail is maintained. Essential documents are retained in the Trial Master File (TMF-IDX) for the period required by regulation. Datasets and metadata are archived to support reproduction and inspection.

15. Publication Policy

Study results will be published in accordance with the sponsor's publication policy and ICMJE recommendations; the trial is registered on applicable public registries; the primary multicentre publication precedes any single-site publication.

16. References

ICH E3, E6(R3), E8(R1), E9, E9(R1), E2A; Investigator's Brochure (IB-001); Clinical Program Parameters (REF-002); Statistical Analysis Plan (SAP-301); Clinical Study Report (CSR-301); Risk Management Plans (RMP-EU/US/KR); TMF operational documents (TMF-DMP/CMP/DSMB/RAND/PHARM/LAB/SMP).

Appendix A — Schedule of Activities (Footnotes)

The Schedule of Activities is presented in §8. Operational footnotes: (1) all efficacy and safety analytes are measured at the central laboratory (TMF-LAB); (2) fasting (≥8 h) is required for FPG and lipid assessments; (3) the analysis visit window is ±7 days from the nominal week, with the Week-52 visit being the primary endpoint timepoint; (4) vital signs are measured after ≥5 minutes of seated rest; (5) unscheduled visits may be performed at any time for safety assessment, with the assessments performed recorded against an unscheduled visit; (6) for any subject who discontinues study treatment but remains in the study, the Week-52 and follow-up assessments are performed per the SoA wherever possible (treatment-policy estimand, §3.1).

Appendix B — AESI Definitions and SAE Reporting Flow

B.1 AESI Definitions and Actions

AESI	Operational definition	Monitoring / action
Gastrointestinal events	Nausea, vomiting, diarrhoea (MedDRA PT)	Titration/dose modification (§6.3); follow severe/persistent events to resolution
Acute pancreatitis	Clinical suspicion + lipase/amylase >3×ULN and/or imaging	Discontinue IMP; confirm and adjudicate; report as AESI/SAE if serious
Thyroid C-cell / MTC	Elevated calcitonin or thyroid mass	Endocrinology referral; calcitonin/imaging follow-up; adjudicate
Hypoglycaemia	Plasma glucose <3.9 mmol/L or symptoms (see Appendix E)	Classify Level 1–3; record glucose; manage; report severe (Level 3) as AESI/SAE
Cardiovascular / heart-rate	Sustained HR increase, arrhythmia, or CV event	Vital-sign/ECG surveillance; cardiology referral as needed

B.2 SAE Reporting Flow

1. Site identifies an SAE → records on the eCRF and the SAE report form.
2. Site notifies the sponsor pharmacovigilance function within 24 hours of awareness.
3. Sponsor PV assesses seriousness, expectedness (against the IB reference safety information, IB-001 §7), and causality.
4. Expedited regulatory reporting of SUSARs: 7 calendar days (fatal/life-threatening) or 15 calendar days (other serious), to regulators, IRBs/IECs, and investigators, per ICH E2A and regional requirements.
5. Follow-up reports are submitted until resolution/stabilization; periodic aggregate reporting (DSUR) is performed during development (TMF-SMP).

Appendix C — Dose-Modification and Titration-Management Algorithm

At each titration step (Week 4, Week 8):
  Tolerable (no/limited GI AE)            → advance to next dose step as scheduled.
  Intolerable GI AE at current step       → option 1: delay step-up by up to 4 weeks
                                            option 2: down-titrate one dose level,
                                                      then re-attempt escalation later.
  Recurrent intolerance despite the above → permanently discontinue IMP.
  Confirmed pancreatitis / suspected MTC  → permanently discontinue IMP.
  Severe hypersensitivity / pregnancy     → permanently discontinue IMP.
Subjects who discontinue IMP continue study assessments where possible.

Appendix D — Rescue-Medication Criteria and Procedures

Rescue antihyperglycaemic therapy (per local standard of care; GLP-1 receptor agonists are not permitted as rescue) may be initiated when, on a repeat/confirmed measurement, any of the following thresholds are met:

Period	Threshold
Weeks 0–12	FPG > 15.0 mmol/L
After Week 12	FPG > 13.3 mmol/L
After Week 24	HbA1c > 9.0%
The randomized IMP is continued where possible. Initiation of rescue constitutes an intercurrent event handled under the hypothetical strategy for the primary estimand (post-rescue values set to missing; §3.1), with a treatment-policy sensitivity analysis retaining post-rescue data (SAP-301 §3.2).

Appendix E — Hypoglycaemia Classification and Management

Level	Definition	Recording / management
Level 1	Glucose 3.0–<3.9 mmol/L	Record glucose; oral carbohydrate; review concomitant secretagogue/insulin dose
Level 2	Glucose <3.0 mmol/L	As above; closer monitoring
Level 3 (severe)	Event with altered mental/physical status requiring assistance	Treat urgently; report as AESI/SAE; assess causality; consider dose review/discontinuation
All episodes are recorded with date/time, glucose value (where available), symptoms, treatment, and outcome.

Appendix F — Contraception Requirements (WOCBP)

A woman of childbearing potential (WOCBP) is a fertile female who is not permanently sterilized and not postmenopausal (≥12 months amenorrhoea without alternative cause). WOCBP must use a highly effective contraceptive method (e.g., combined or progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device/system, bilateral tubal occlusion, vasectomized partner, or sexual abstinence) from screening through the follow-up visit. Pregnancy testing (serum at screening; serum/urine per the SoA) is performed; any pregnancy results in IMP discontinuation and follow-up of the pregnancy outcome (TMF-SMP).

Appendix G — Clinical Laboratory Parameters, Units, and Reference Ranges

Parameter	Unit	Reference range (illustrative)	Alert/critical
HbA1c	%	4.0–5.6 (non-diabetic)	>12.0 → review
Fasting plasma glucose	mmol/L	3.9–5.5	<3.0 / >20
ALT	U/L	≤40 (ULN)	>3× ULN → AESI (EDC-007)
AST	U/L	≤40 (ULN)	>3× ULN
eGFR (CKD-EPI)	mL/min/1.73m²	≥90 normal	<45 post-baseline → notable (EDC-006)
Haemoglobin	g/dL	sex-specific	per lab
NT-proBNP / hsCRP	per assay	per assay	per assay [MOCK]
Reference ranges and alert/critical values are maintained and versioned by the central laboratory (TMF-LAB) and provided to sites.

Appendix H — SPIRIT 2013 Checklist (Mapping)

SPIRIT item (group)	Protocol location
Administrative (title, registration, sponsor, roles)	Title page; §4.7; Sponsor Signature Page
Introduction (background, objectives)	§1; §2
Methods — participants/interventions/outcomes	§5; §6; §2; §9
Methods — assignment (randomization, blinding)	§6.4; §4.2
Methods — data collection/management/analysis	§8; §9; §11; §12
Methods — monitoring (DSMB, harms, auditing)	§4.7; §7.3; §10; §12
Ethics & dissemination	§13; §15
Appendices (consent, biological specimens)	TMF-ICF; §9.3

Appendix I — Protocol Amendment History

No protocol amendments have been issued; the document version history is recorded in the Change History above. Future amendments will be summarized here with rationale, affected sections, and IRB/IEC approval status, and tracked in the deviation/issue logs (QA-DEV / QA-ISSUE).