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

Phase 2

Recruiting

• Conditions: Kidney Transplant Recipients
• Interventions: Drug: Dapagliflozin 10 MG; Drug: Semaglutide, 1.0 mg/mL

• Registration Number: NCT05938712
• Lead Sponsor: University Health Network, Toronto

Brief Summary

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.

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 Timeline

• Study First Submitted: 2023-05-16
• Status Verified: 2023-07
• Study First Submitted QC: 2023-07-06
• Study First Posted: 2023-07-10
• Study Start: 2023-10-24
• Last Update Submitted: 2023-11-29
• Last Update Posted: 2023-12-06
• Primary Completion: 2025-10-01
• Study Completion: 2025-10-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 20

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%;

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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.).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Semaglutide	Dapagliflozin 10 MG	Semaglutide Subcutaneous 0.25mg once weekly for 4 weeks, then 0.5mg once weekly for 4 weeks, then 1mg once weekly for 4 weeks.
Semaglutide	Semaglutide, 1.0 mg/mL	Semaglutide Subcutaneous 0.25mg once weekly for 4 weeks, then 0.5mg once weekly for 4 weeks, then 1mg once weekly for 4 weeks.
Dapagliflozin	Dapagliflozin 10 MG	Dapagliflozin Tablets Total Dose 10mg daily for 12 weeks
Dapagliflozin	Semaglutide, 1.0 mg/mL	Dapagliflozin Tablets Total Dose 10mg daily for 12 weeks

Primary Outcome Measures

Name	Time	Method
Proximal tubular natriuresis with combination therapy	From baseline to combination therapy end (24 weeks)	Measured by fractional excretion of sodium
Proximal tubular natriuresis with monotherapy	From baseline to monotherapy end (12 weeks)	Measured by fractional excretion of sodium

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Toronto General Hospital; 🇨🇦 Toronto, Ontario, Canada