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

Diabetes Mellitus, Type 1 Clinical Trial

— PLUTO  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06147232
• Other study ID #: EUCT 2023-509450-55-00
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: August 2024
• Est. completion date: June 2036

Study information

• Verified date: November 2023
• Source: Steno Diabetes Center Copenhagen
• Contact: Mette Brouw Iversen, MD
• Phone: +4529267717
• Email: mette.brouw.iversen[@]regionh.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 69
• Est. completion date: June 2036
• Est. primary completion date: June 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Albuminuria
• Diabetes Complications
• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Diabetic Complications Renal
• Diabetic Nephropathies
• Hypoxia
• Kidney Diseases
• Nephropathy

Intervention

Drug:
• Sotagliflozin
Sodium-glucose-co-transporter 1 and 2 inhibitor
• Placebo
Placebo tablet

Locations

Country	Name	City	State
Denmark	Steno Diabetes Center Copenhagen	Herlev

Sponsors (4)

Lead Sponsor	Collaborator
Steno Diabetes Center Copenhagen	Glostrup University Hospital, Copenhagen, Juvenile Diabetes Research Foundation, King's College London

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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