Efficacy, Mechanisms and Safety of SGLT2 Inhibitors in Kidney Transplant Recipients

NCT ID: NCT04965935

Last Updated: 2025-03-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-07-15
• Study Completion Date: 2024-08-30

Brief Summary

This study will be a randomized, double-blind, placebo-controlled clinical trial comparing the SGLT2 inhibitor dapagliflozin to placebo in 52 kidney transplant recipients (KTR) with or without pre-existing type 2 diabetes (T2D) or post-transplant diabetes mellitus (PTDM). The primary outcome of the trial is to determine if dapagliflozin is superior to placebo in reduction of blood pressure in KTR.

Detailed Description

Kidney transplantation is the renal replacement therapy of choice for patients with end stage renal disease (ESRD). It has been well established that kidney transplantation improves patient survival and quality of life, and results in significant savings to the health care system.

Despite the survival benefit conferred by transplantation, KTR still face a number of challenges, especially in patients with diabetes. First, KTR still have a higher risk of mortality than their age-matched counterparts without kidney disease. This mortality risk is even greater amongst KTR with diabetes. Furthermore, mortality from cardiovascular disease (CVD) continues to be an important problem after transplantation. Another major challenge faced by KTR is the continuing risk of developing graft failure over time. Unfortunately, in the subgroup of KTR with diabetes, the incidence of graft failure is 50% higher than the general kidney transplant recipient population, and recurrent diabetic kidney disease (DKD) occurs in almost half of allografts after transplantation. Current strategies in the management of graft dysfunction and chronic kidney disease (CKD) are focused on optimizing immunosuppression and control of hypertension and dyslipidemia. Accordingly, there is an important unmet need for cardio- and renoprotective strategies to address premature death and graft loss in the KTR population.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are glucose lowering agents that are effective in the treatment of T2D, resulting not only in improved glycemic control, but also weight loss, blood pressure and albuminuria reduction. Several clinical trials have shown significant benefits of SGLT2i on cardiovascular and renal outcomes. Given the glucose-dependent and independent effects of SGLT2i, as well as the accumulating evidence demonstrating cardiorenal protection in non-KTR, the use of these agents in KTR is attractive - especially since traditional renin-angiotensin-aldosterone system inhibitors are not effective. Moreover, the use of SGLT2i as a cardiorenal protective therapy may be of particular value in KTR given the high burden of comorbidities such as diabetes, CVD and hypertension, as well as the ongoing challenges of premature death and graft loss in this population.

This study will be a randomized, double-blind, placebo-controlled clinical trial comparing the SGLT2 inhibitor dapagliflozin to placebo in 52 KTR with or without pre-existing T2D or PTDM. The primary outcome of the trial is to determine if dapagliflozin is superior to placebo in reduction of blood pressure in KTR. The secondary outcomes of this study include metabolic, vascular, renal and transplant-specific measures. These outcomes have been included to elucidate the potential mechanisms responsible for blood pressure lowering, and putative cardio- and renoprotective effects in KTR. Safety outcomes will also be assessed.

Conditions

Kidney Transplant Recipients; Post-transplant Diabetes Mellitus; Type 2 Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Dapagliflozin Tablets

Patients will be randomized to therapy with dapagliflozin 10mg PO daily for 12 weeks.

Group Type: EXPERIMENTAL

Dapagliflozin 10 MG Oral Tablet

Intervention Type: DRUG

Dapagliflozin will be administered in a dose of 10 mg/day for 12 weeks.

Placebo Matching Dapagliflozin Tablets

Patients will be randomized to therapy with placebo matching dapagliflozin tablets PO daily for 12 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo Matching Dapagliflozin Oral Tablet

Intervention Type: DRUG

Placebo will be administered for 12 weeks.

Interventions

Dapagliflozin 10 MG Oral Tablet

Dapagliflozin will be administered in a dose of 10 mg/day for 12 weeks.

Intervention Type: DRUG

Placebo Matching Dapagliflozin Oral Tablet

Placebo will be administered for 12 weeks.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Male or females >18 years old ≥ 6months after kidney transplantation;

2. In patients with T2D or PTDM, HbA1c <12.0%;

3. eGFR ≥30 ml/min/1.73m^2 (as per the CKD-EPI equation);

4. BMI ≤45kg/m^2;

5. Blood pressure ≤160/90 and ≥90/60 at screening.

Exclusion Criteria

1. Diagnosis of type 1 diabetes;

2. Presence of severe peripheral vascular disease (i.e. prior amputation, gangrene, non-healing ulcer or ischemic rest pain);

3. Presence of acute coronary syndrome, stroke or transient ischemic attack in the 3 months prior to screening;

4. Prior episode of graft pyelonephritis in the 1 month prior to screening;

5. Episode of acute graft rejection in the 3 months prior to screening;

6. Initiation of a new immunosuppressive agent or discontinuation of an immunosuppressive agent in the 1 month prior to screening;

7. Untreated urinary or genital tract infection;

8. Severe hypoglycemia within 3 months of screening, or hypoglycemia unawareness;

9. Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control;

10. Participation in another trial with an investigational drug within 30 days of informed consent;

11. Alcohol or drug abuse within 3 months prior to informed consent that would interfere with trial participation;

12. Any ongoing clinical condition that would jeopardize subject safety or study compliance based on investigator judgement.

13. Patients currently using antipsychotic medications.

14. Use of SGLT2 inhibitors within 1 month of starting the study.

• Minimum Eligible Age: 19 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Health Network, Toronto

OTHER

Sponsor Role: lead

Responsible Party

Sunita Singh, MD, MSc, FRCPC

Clinician Scientist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Sunita KS Singh, MD MSc FRCPC

Role: PRINCIPAL_INVESTIGATOR

University Health Network, Toronto General Hospital

Locations

Renal Physiology Laboratory

Toronto, Ontario, Canada

Countries

Canada

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

19-5342

Identifier Type: -

Identifier Source: org_study_id