Clinical trial NCT06147232: Prevention of Chronic Kidney Disease(CDK) Progression in Type 1 Diabetes With Long Term Use of Sodium-Glucose-coTransporter Inhibitors Avoiding Kidney hypOxia
Official title: Prevention of CKD Progression in Type 1 Diabetes With Long Term Use of SGLTi Avoiding Kidney hypOxia(PLUTO)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Nephropathy
Diabetic Nephropathies
Diabetes Mellitus, Type 1
Albuminuria
Diabetic Complications Renal
Diabetic Complications Cardiovascular
Hypoxia
Lead sponsor: Steno Diabetes Center Copenhagen
Sponsor class: OTHER
Collaborators: name: Juvenile Diabetes Research Foundation
name: King's College London
name: Glostrup University Hospital, Copenhagen
name: Guy's and St Thomas' NHS Foundation Trust
First posted: 2023-11-27
Enrollment: 69
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: randomized, double-blinded, placebo-controlled, cross-over intervention study
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Change in dynamic R2*-weighted signal (BOLD) as an indirect measure of renal blood oxygenation
timeFrame: 0 to 12 weeks in both treatment arms, last measure 30 weeks after randomization.
Secondary outcomes:
measure: Change in renal perfusion (medullary and cortical)
timeFrame: From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization
measure: Change in renal artery flow
timeFrame: From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization
measure: Change in renal oxygen consumption
timeFrame: From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization
measure: Change in renal parenchymal triglyceride fraction
timeFrame: From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization
measure: Change in renal fibrosis
timeFrame: From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization
measure: Change in left ventricular ejection fraction
timeFrame: From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization
measure: Change in albuminuria
timeFrame: From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization.
measure: Change in levels of ketone bodies
timeFrame: From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization.
measure: Change in plasma and urine inflammation- and fibrosis biomarkers
timeFrame: From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization.
measure: Change in endogenous erythropoietin
timeFrame: From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization.
measure: Change in pro brain natriuretic peptide
timeFrame: From 0 to 12 weeks in each treatment arm. Last measure 30 weeks after randomization.
measure: Difference in Kidney Function after 12 weeks treatment with sotagliflozin vs placebo
timeFrame: From 12 to 30 weeks after randomization
Other outcomes:
measure: Ethnicity
timeFrame: From baseline to 30 weeks.
Locations:
city: Herlev
country: Denmark
facility: Steno Diabetes Center Copenhagen
city: London
country: United Kingdom
facility: Guy's and St Thomas NHS Trust
Study officials:
References: