Prevention of Chronic Kidney Disease(CDK) Progression in Type 1 Diabetes With Long Term Use of Sodium-Glucose-coTransporter Inhibitors Avoiding Kidney hypOxia (PLUTO)

Prevention of CKD Progression in Type 1 Diabetes With Long Term Use of SGLTi Avoiding Kidney hypOxia(PLUTO)

Background: Sodium-glucose-cotransporter (SGLT) inhibition has been observed to reduce risk of cardiovascular events and kidney failure in persons with type 2 diabetes. People with type 1 diabetes also have increased risk of cardiovascular and kidney disease, and may benefit from SGLT-inhibition. The exact mechanism of how SGLT-inhibition benefits the kidneys are yet unknown. Change in renal hypoxia may be a factor.

Objective: The primary aim of this study is to assess the effects of 12 weeks SGLT-1 and 2 inhibition on renal oxygenation in persons with type 1 diabetes and chronic kidney disease.

Further aims are to study if renal oxygen consumption and response to SGLT-inhibition differs between people of African-Caribbean or Northern European decent.

Additionally effects on left ventricular ejection fraction, kidney function and biomarkers in blood and urine will be explored.

Method: 12 weeks treatment with oral sotagliflozin or matching placebo as intervention. Kidney oxygenation and perfusion parameters and left ventricular ejection fraction will be assessed by functional magnetic resonance imaging. Kidney function and biomarkers will be assessed according to local hospital laboratory guidelines.

Design: Randomized, double-blinded, placebo-controlled, cross over intervention study.

Study population: 69 persons with type 1 diabetes and diabetic kidney disease with albuminuria will be included, 39 at Steno Diabetes Center Copenhagen, 30 at King's College London.

Endpoints: Primary end-point: Change from 0 to 12 weeks in dynamic R2*-weighted signal after treatment with sotagliflozin compared to placebo. Secondary endpoints: Change from 0 to 12 weeks with sotagliflozin compared with placebo on renal perfusion, renal artery flow, renal oxygen consumption, renal parenchymal triglyceride fraction, renal fibrosis, left ventricular ejection fraction, urinary albumin-creatinin ratio, ketone bodies, erythropoietin, pro brain natriuretic peptide, and plasma- and urine inflammation- and fibrosis biomarkers as well as difference after 12 weeks treatment in glomerular filtration rate.

Timeframe: Inclusion of patients from february 2024. Last visit september 2025. Presentation spring 2026, publication fall 2026.

Study Overview

• Status: Not yet recruiting
• Conditions: Hypoxia; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Albuminuria; Nephropathy; Diabetic Complications Renal; Diabetic Complications Cardiovascular
• Intervention / Treatment: Drug: Placebo; Drug: Sotagliflozin

• Study Type: Interventional
• Enrollment (Estimated): 69
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Mette Brouw Iversen, MD; Phone Number: +4529267717; Email: mette.brouw.iversen@regionh.dk
• Study Contact Backup: Name: Peter Rossing, MD, DMSc; Phone Number: +4530913383; Email: peter.rossing@regionh.dk

Study Locations

• Denmark
  • Herlev, Denmark, 2730
    • Steno Diabetes Center Copenhagen
    • Contact: Mette Brouw Iversen, MD; Phone Number: 004529267717; Email: mette.brouw.iversen@regionh.dk
    • Contact: Elisabeth Stougaard, MD, PhD; Phone Number: 004522436292; Email: elisabeth.buur.stougaard@regionh.dk
    • Principal Investigator: Peter Rossing, MD
    • Sub-Investigator: Mette Brouw Iversen, MD
    • Sub-Investigator: Elisabeth Stougaard, MD
    • Sub-Investigator: Emilie Frimodt-Moeller, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Persons ≥ 18 years of age with a diagnosis of type 1 diabetes (age at onset <40 years; permanent insulin treatment initiated within 1 year of diagnosis)
2. Albuminuria: UACR > 100 mg/g (in ≥2 out 3 morning spot urine collections prior to randomization)
3. estimated Glomerular Filtration Rate(eGFR) ≥25 and < 75 ml/min/1.73m2
4. Participants must be on stable renin-angiotensin system blocking treatment 4 weeks before start of study drug and throughout study duration.
5. Able to understand the written participant information and give informed consent

Exclusion Criteria:

1. Non-diabetic kidney disease indicated by medical history and/or laboratory findings.
2. eGFR< 25 ml/min/1.73m2, dialysis or kidney transplantation.
3. Previous diabetic ketoacidosis, except at debut.
4. Dysregulated diabetes (HbA1c > 85 mmol/mol)
5. Decreased awareness or unawareness
6. Pregnancy, lactating or with a wish of pregnancy within the next year
7. Low carbohydrate diet
8. Receiving therapy with an SGLT inhibitor within 8 weeks prior to enrolment or previous intolerance of an SGLT inhibitor.
9. New York Heart Association (NYHA) class IV Congestive Heart Failure at the time of enrolment
10. Myocardial infarction, unstable angina, stroke or transient ischemic attack within 12 weeks prior to enrolment
11. The receipt of any investigational product 90 days prior to this trial
12. Unable to participate in study procedures
13. Any clinically significant disorder, except for conditions associated with type 1 diabetes, which in the Investigators opinion could interfere with the results of the trial
14. Participation in another intervention study
15. Exclusion criteria for MRI: known claustrophobia, known chronic lung disease, surgery within past 6 weeks or having foreign bodies of metal in the body (e.g. pacemaker, metal plates, metal screws)
16. Recurrent urogenital infections.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sotagliflozin; In the active arm, participants will be treated with Sotagliflozin 200mg as an oral tablet once daily for 12 weeks.	Drug: Sotagliflozin; Sodium-glucose-co-transporter 1 and 2 inhibitor; Other Names: Inpefa (TM)
Placebo Comparator: Placebo; In the placebo arm, participants will be treated with a matched placebo as an oral tablet once daily for 12 weeks.	Drug: Placebo; Placebo tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in dynamic R2*-weighted signal (BOLD) as an indirect measure of renal blood oxygenation	difference between change from 0 to 12 weeks after treatment with sotagliflozin compared to treatment with placebo	0 to 12 weeks in both treatment arms, last measure 30 weeks after randomization.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in renal perfusion (medullary and cortical)	Measured with MRI by arterial spin labelling in mL/g/min	From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization
Change in renal artery flow	Renal artery flow measured by using phase contrast (PC) MRI. It is measured in mL/min.	From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization
Change in renal oxygen consumption	Renal oxygen consumption measured by MRI with T2-relaxation-under-spin-tagging.	From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization
Change in renal parenchymal triglyceride fraction	Renal parenchymal triglyceride fraction is measured by MRI spectroscopy	From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization
Change in renal fibrosis	Renal fibrosis is measured by MRI-derived apparent diffusion coefficient	From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization
Change in left ventricular ejection fraction	Left ventricular ejection fraction is assessed by MRI	From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization
Change in albuminuria	Urinary albumin-creatinine ratio (UACR) - morning void spot urine samples collected at home by participants.	From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization.
Change in levels of ketone bodies	Capillary blood ketones, possibly measured by continous ketone monitoring device	From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization.
Change in plasma and urine inflammation- and fibrosis biomarkers	Measured from blood and urine samples using a commercially available panel from the company Olink. Includes 92 biomarkers.	From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization.
Change in endogenous erythropoietin	Analysis on blood samples at regional hospital laboratory.	From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization.
Change in pro brain natriuretic peptide	Analysis on blood samples at regional hospital laboratory.	From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization.
Difference in Kidney Function after 12 weeks treatment with sotagliflozin vs placebo	Glomerular filtration rate. At Steno Diabetes Center Copenhagen this will be measured by plasma clearance of Tc-99m diethylene-triamine-pentaacetate.	From 12 to 30 weeks after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ethnicity	if African-Caribbean ethnicity is associated with any of the above secondary outcomes or baseline differences in cardio-renal disease markers/imaging measures	From baseline to 30 weeks.

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: King's College London; Juvenile Diabetes Research Foundation; Glostrup University Hospital, Copenhagen

Study record dates

Study Major Dates

• Study Start (Estimated): August 1, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2036

Study Registration Dates

• First Submitted: November 19, 2023
• First Submitted That Met QC Criteria: November 19, 2023
• First Posted (Actual): November 27, 2023

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: April 22, 2024
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Urologic Diseases; Urological Manifestations; Endocrine System Diseases; Urination Disorders; Signs and Symptoms, Respiratory; Proteinuria; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Diabetes Mellitus; Kidney Diseases; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Albuminuria; Hypoxia; Diabetes Complications; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol
• Other Study ID Numbers: EUCT 2023-509450-55-00

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
• product manufactured in and exported from the U.S.: No