The Efficacy, Mechanism & Safety of Sodium Glucose Co-Transporter-2 Inhibitor & Glucagon-Like Peptide 1 Receptor Agonist Combination Therapy in Kidney Transplant Recipients (HALLMARK)

A Two Arm, Open Label, Pilot Study to Evaluate the Safety and Efficacy of the Combined Use of Once Daily 10mg Dapagliflozin and Once Weekly 1.0mg Semaglutide in Kidney Transplant Recipients

The study aims to determine the short-term efficacy, mechanisms and safety of 12 weeks of dapagliflozin and semaglutide combination therapy in 20 KTR, with and without T2D.

Study Overview

• Status: Recruiting
• Conditions: Kidney Transplant Recipients
• Intervention / Treatment: Drug: Dapagliflozin 10 MG; Drug: Semaglutide, 1.0 mg/mL

Detailed Description

Kidney transplantation improves survival and quality of life for patients with kidney failure. However, treatment options to protect the heart and the kidney in transplant recipients are lacking. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) are novel anti-diabetic drugs which not only lower blood sugar, but also lower blood pressure in the kidney's individual filtering units and protect kidney function in the long term. It is unclear if the protective mechanisms of these drugs also occur in people with a kidney transplant. Several smaller studies have shown that SGLT2 inhibitors or GLP-1RA used alone are safe in people with kidney transplants. No studies have yet to look at the combined use of SGLT2 inhibitors and GLP-1RA in kidney transplant recipients (KTR).

The purpose of the HALLMARK study is to determine the mechanisms and safety of the combination use of semaglutide, a GLP-1RA, and dapagliflozin, a SGLT2 inhibitor. To investigate this, 20 kidney transplant recipients with and without diabetes will be treated with both semaglutide or dapagliflozin for 12 weeks followed by a combination of semaglutide and dapagliflozin for 12 weeks. The study will measure salt and water removal as well as the effect on blood pressure, kidney function, heart function, liver stiffness as well as the safety of these agents.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Vesta Lai; Phone Number: 8508 416-340-4800; Email: vesta.lai@uhn.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2N2
      • Recruiting
      • Toronto General Hospital
      • Contact: Vesta Lai; Phone Number: 8508 416-340-4800; Email: vesta.lai@uhn.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed and dated written informed consent.
• Patients aged ≥18 years with KTR
• >3 months post kidney transplantation
• Estimated glomerular filtration rate [eGFR] ≥20 ml/min/1.73m2
• BP <160/100 and >90/60 at screening
• Body-mass index [BMI] between 18.5-40kg/m2
• In patients with T2D or PTDM, HbA1c <12.0%;

Exclusion Criteria:

• Type 1 diabetes.
• History of multi-organ transplant
• Acute coronary syndrome, transient ischemic attack or stroke within 30 days prior to screening
• Impending need for kidney biopsy or rapid decline in eGFR within 30 days prior to screening
• Actively treated BK, CMV or EBV infection
• Recurrent pyelonephritis or need for indwelling or self-catheterization
• Prior amputation or ischemic rest pain
• Women who are pregnant, nursing, or who plan to become pregnant whilst in the trial.
• History of pancreatitis
• Personal or family history or medullary thyroid cancer or MEN2B
• History of unstable diabetic retinopathy within 1 year prior to screening
• Use of SGLT2i or GLP-1RA within 30 days prior to screening.
• Current and frequent episodes of hypoglycemia
• Current history of DKA requiring medical intervention or hospitalization
• With current risk of volume depletion, hypotension and/or electrolyte imbalance
• With known or suspected hypersensitivity to semaglutide or related products
• Patient not able to understand and comply with study requirements, based on Investigator's judgment.
• Any other clinical condition that, based on Investigator's judgement, would jeopardize patient safety during trial participation or would affect the study outcome (e.g. immunocompromised patients, active malignancy, patients who might be at higher risk of developing genital or mycotic infections, patients with chronic viral infections, uncontrolled hypertension, cardiorenal and/or hepatorenal syndrome etc.).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Semaglutide; Semaglutide Subcutaneous 0.25mg once weekly for 4 weeks, then 0.5mg once weekly for 4 weeks, then 1mg once weekly for 4 weeks.	Drug: Dapagliflozin 10 MG; Semaglutide subcutaneous once weekly for 12 weeks.; Other Names: FARXIGA; Drug: Semaglutide, 1.0 mg/mL; Dapagliflozin oral once daily for 12 weeks.; Other Names: OZEMPIC
Experimental: Dapagliflozin; Dapagliflozin Tablets Total Dose 10mg daily for 12 weeks	Drug: Dapagliflozin 10 MG; Semaglutide subcutaneous once weekly for 12 weeks.; Other Names: FARXIGA; Drug: Semaglutide, 1.0 mg/mL; Dapagliflozin oral once daily for 12 weeks.; Other Names: OZEMPIC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proximal tubular natriuresis with combination therapy	Measured by fractional excretion of sodium	From baseline to combination therapy end (24 weeks)
Proximal tubular natriuresis with monotherapy	Measured by fractional excretion of sodium	From baseline to monotherapy end (12 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measured Glomerular Filtration Rate	GFR, based on plasma iohexol clearance	From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Estimated Glomerular Filtration Rate	GFR, based on serum creatinine	From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Urinary 8-hydroxydeoxyguanosine and 8-isoprostane concentration	Using ELISA	From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Urinary albumin excretion	From 24-hour urine collection	From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Arterial stiffness	Measured using a Sphygmocor device	From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Liver stiffness	Using transient elastography	From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Diastolic function	Using 2D echocardiography	From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Change in percentage of glycated hemoglobin (HbA1c)		From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Change in concentration of urine glucose excretion	Urinary analysis will be performed to quantify the amount of glucose excretion.	From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Change in body composition (percent body mass, body fat, and muscle mass)	Bioimpedence measurements will be taken to study the effects of intervention on body composition.	From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Change in body weight		From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Safety: the incidence of acute kidney injury.		From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Safety: the incidence of hypotension		From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Safety: The incidence of hyperkalemia		From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Safety: The incidence of urinary and mycotic infections.		From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Safety: The number of ketoacidosis events.		From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Safety: The incidence of amputations.		From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Safety: The incidence of pancreatitis or biliary complications		From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]
Safety: The number of allergic reaction events.		From baseline to monotherapy end (12 weeks) and combination therapy end (24 weeks) ]

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Investigators: Principal Investigator: Sunita Singh, MD MSc FRCPC, University Health Network, Toronto General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2023
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: May 16, 2023
• First Submitted That Met QC Criteria: July 6, 2023
• First Posted (Actual): July 10, 2023

Study Record Updates

• Last Update Posted (Actual): May 1, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Type 2 diabetes; SGLT2 inhibition; GLP-1 receptor agonist
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2 Inhibitors; Glucagon-Like Peptide-1 Receptor Agonists; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hypoglycemic Agents; semaglutide; dapagliflozin
• Other Study ID Numbers: 23-5050

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No