Sotagliflozin Safety and Tolerability Among Renal Transplant Recipients

Study Overview
=================
Brief Summary
-----------------
This is an investigator-initiated, randomized controlled trial in adult KTRs (N=50) with stable allograft function to assess: 1) the reversibility of the expected acute changes in eGFR with sotagliflozin (donated by Lexicon); 2) proportion of patients completing the protocol according to different eGFR reporting strategies (using a predefined algorithm to manage the expected pharmacological effect of sotagliflozin on eGFR); 3) safety and tolerability of sotagliflozin.

Official Title
-----------------
Sotagliflozin Safety and Tolerability Among Renal Transplant Recipients

Conditions
-----------------
Kidney Transplant

Intervention / Treatment
-----------------
* Diagnostic Test: eGFR reporting


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults ≥18 years Recipients of kidney transplant with stable eGFR* eGFR-creatinine (CKD-EPI 2021) ≥25 mL/min/1.73 m2 Informed consent Stable eGFR will be ascertained by careful chart review establishing that the patient's current graft has been functioning for at least 12 months post-transplantation, patients have not been treated for acute rejection within the prior 3 months, and a creatinine-based eGFR is stable (two consecutive measurements separated by at least 28 days within 5 mL/min/1.73 m2) and ≥25 mL/min/1.73 m2. Exclusion Criteria: Recurrent urinary tract infections (>2 episodes/year or antibiotic prophylaxis) Biopsy-proven acute rejection within 12 weeks Screening serum potassium >5.5 mmol/L Uncontrolled hypertension (systolic blood pressure >180/100 mmHg) New York Heart Association (NYHA) Class IV HF Myocardial infarction, unstable angina, revascularization procedure (e.g., stent or bypass graft surgery), or cerebrovascular accident within 12 weeks History of diabetic ketoacidosis Type 1 Diabetes Mellitus Hereditary glucose-galactose malabsorption or primary renal glucosuria Liver disease (e.g., acute hepatitis, chronic active hepatitis, cirrhosis); Alanine aminotransferase (ALT) levels >2.0 times the upper limit of normal (ULN) or total bilirubin >1.5 times the ULN, unless consistent with Gilbert's disease Malignancy within 5 years (exceptions: squamous and basal cell carcinomas of the skin and carcinoma of the cervix in situ, or a malignancy that in the opinion of the investigator is considered cured with minimal risk of recurrence) Human immunodeficiency virus antibody positive Major surgery within 12 weeks Atraumatic amputation within past 12 months of screening, or an active skin ulcer, osteomyelitis, gangrene, or critical ischemia of the lower extremity within 6 months of screening Combination use of ACEi and ARB Current use of an SGLT2 inhibitor (within 12 weeks prior to randomization) Known allergies, hypersensitivity, or intolerance to SGLT2i or its excipients Digoxin plasma level >1.2 ng/mL Clofibrate, fenofibrate, dronedarone, or ranolazine treatment that has not been at a stable dose in the 30 days prior to screening or randomization, or a dose adjustment is expected Received an active investigational drug (including vaccines) other than a placebo agent, or used an investigational medical device within 12 weeks before Day 1/baseline Pregnant or breast-feeding or planning to become pregnant or breast-feed during the study Women of childbearing potential not willing to use a highly-effective method(s) of birth control, or who are unwilling or unable to be tested for pregnancy Any condition that in the opinion of the investigator would make participation not in the best interest of the subject

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A pre-defined algorithm for suggested management of acute changes in eGFR will be provided to all treating physicians. To test the proportion of patients successfully completing the protocol according to two different eGFR reporting strategies, randomization at the patient level will occur as follows: only study-related eGFR values >25% below baseline will be reported to patients and providers all study-related eGFR values will be provided to patients and providers
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Patients and providers only aware of study eGFR values more than 25% below baseline<br>Any study-related eGFR value more than 25% below the baseline measurement will be reported to the patient and treating physician. | Diagnostic Test: eGFR reporting<br>* To test the proportion of patients successfully completing the protocol according to different eGFR reporting strategies, randomization in a 1:1 fashion at the patient level (n=50) will occur as follows: only study-related eGFR values >25% below baseline will be reported to patients and providers all study-related eGFR will be provided to patients and providers<br>|
| Other: Patients and providers aware of all study eGFR values<br>All study-related eGFR measurements will be reported to the treating physician and patient. | Diagnostic Test: eGFR reporting<br>* To test the proportion of patients successfully completing the protocol according to different eGFR reporting strategies, randomization in a 1:1 fashion at the patient level (n=50) will occur as follows: only study-related eGFR values >25% below baseline will be reported to patients and providers all study-related eGFR will be provided to patients and providers<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reversibility of eGFR changes | Following 12 weeks of open-label drug treatment, participants will stop drug and be followed for a further four weeks (16 weeks total). Reversibility will be assessed as the proportion of patients who return to baseline eGFR (+/- 10%) by the end of the 4-week off-treatment period. | 16 weeks total | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients successfully completing the full treatment protocol, according to randomized groups | Following 12 weeks of open-label drug treatment, participants will stop drug and be followed for a further four weeks. The proportion of patients completing the full 16 weeks will be compared according to randomized groups. | 16 weeks total |