A Research Study to Find Out How Semaglutide Works in the Kidneys Compared to Placebo, in People With Type 2 Diabetes and Chronic Kidney Disease (the REMODEL Trial)

Study Overview
=================
Brief Summary
-----------------
We are doing this study to learn more about how semaglutide may help fight chronic kidney disease in people with type 2 diabetes. We are doing this by looking into how semaglutide works in the kidneys. Participants will either get semaglutide or placebo (a 'dummy' medicine) - which treatment participants get is decided by chance. Semaglutide is a medicine doctors can prescribe in some countries for the treatment of type 2 diabetes. Participants will get the study medicine in a pen. Participants will use the pen to inject the medicine into the skin once a week. The study will last for about 1 year. Participants will have 11 visits to the clinic, and 2 phone visits. Some of the visits could be in different locations. Study staff will take blood samples at most of these visits. At 9 visits, participants will be asked to bring a sample of their first morning urine. At 4 of the visits participants will have to bring urine that they have collected over the last 24 hours. The study includes magnetic resonance imaging (MRI) scans of participants' kidneys which is a test that shows a detailed picture of organs and other parts inside the body. The scan will last for 30 minutes, and is free of radiation.

Official Title
-----------------
Renal Mode of Action of Semaglutide in Patients With Type 2 Diabetes and Chronic Kidney Disease

Conditions
-----------------
Diabetes Mellitus, Type 2, Chronic Kidney Disease

Intervention / Treatment
-----------------
* Drug: Semaglutide
* Drug: Placebo (Semaglutide)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female. Age above or equal to 18 years at the time of signing informed consent. Diagnosed with T2D (type 2 diabetes) greater than or equal to 180 days prior to the day of screening. HbA1c (glycated haemoglobin) below or equal to 9.0 percent (below or equal to 75 mmol/mol). Depending on biopsy/non-biopsy population: For subjects in the non-biopsy population: Serum creatinine-based eGFR greater than or equal to 30 and below or equal to 75 mL/min/1.73 m^2(CKD-EPI). For subjects in the biopsy sub-population: Serum creatinine-based eGFR greater than or equal to 40 and below or equal to 75 mL/min/1.73 m^2(CKD-EPI). UACR ( Urinary albumin-to-creatinine ratio ) greater than or equal to 20 and below 5000 mg/g. Treatment with maximum labelled or tolerated dose of a renin-angiotensin-aldosterone system (RAAS) blocking agent including an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB)) unless such treatment is contraindicated or not tolerated.Treatment dose must be stable for at least 28 days prior to screening. Exclusion Criteria: Use of any glucagon-like peptide 1 receptor agonist (GLP-1 RA) within 30 days prior to screening. A prior solid organ transplant or awaiting solid organ transplant. Myocardial infarction, stroke, hospitalisation for unstable angina pectoris or transient ischaemic attack within 180 days prior to the day of screening. Presence or history of malignant neoplasms (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) within 5 years prior to the day of screening. Congenital or hereditary kidney diseases including polycystic kidney disease, autoimmune kidney diseases including glomerulonephritis or congenital urinary tract malformations. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy. Verified by a fundus examination performed within the past 90 days prior to screening or in the period between screening and Visit 2. Pharmacological pupil-dilation is a requirement unless using a digital fundus photography camera specified for non-dilated examination. Treatment with systemic anti-inflammatory or immunosuppressant drugs within 90 days prior to screening. Stable treatment with acetylsalicylic acid for prevention of cardiovascular events and occasional use of propionic acid derivatives drugs (e.g. ibuprofen) is allowed. Any contraindication for MRI according to standard checklist used in clinical routine, including claustrophobia or metallic foreign bodies, metallic implants, internal electrical devices, or permanent makeup/tattoos that cannot be declared MR compatible. Combination use of an ACE (angiotensin-converting enzyme) inhibitor and an ARB (angiotensin II receptor blockers).

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semaglutide 1.0 mg OW<br>Once-weekly (OW) Semaglutide administered subcutaneously (s.c., under the skin). | Drug: Semaglutide<br>* Semaglutide given subcutaneously (sc, under the skin) once weekly. Dose gradually increased over 8 weeks from 0.25 to 1.0 mg. The study will last for about 1 year.<br>|
| Placebo Comparator: Placebo (Semaglutide) 1.0 mg OW<br>Once-weekly (OW) placebo (Semaglutide) administered subcutaneously (s.c., under the skin). | Drug: Placebo (Semaglutide)<br>* Placebo (Semaglutide) given subcutaneously (sc, under the skin) once weekly. Dose gradually increased over 8 weeks from 0.25 to 1.0 mg. The study will last for about 1 year.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in kidney oxygenation (cortex), BOLD (blood oxygenation-level dependent) MRI ( magnetic resonance imaging ) | ratio | From baseline (week 0) to end of treatment (week 52) | 
| Change in kidney oxygenation (medulla), BOLD MRI(R2) | ratio | From baseline (week 0) to end of treatment (week 52) | 
| Change in global kidney perfusion (MRI) | ratio | From baseline (week 0) to end of treatment (week 52) | 
| Change in kidney inflammation (cortex), T1 mapping (MRI) | ratio | From baseline (week 0) to end of treatment (week 52) | 
| Change in kidney inflammation (medulla), T1 mapping (MRI) | ratio | From baseline (week 0) to end of treatment (week 52) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in gene expression assessed by single nucleus RNA sequencing (kidney biopsy) | log2 fold-change | From baseline (week 0) to end of treatment (week 52) | 
| Change in glomerular basement membrane width (kidney biopsy) | nm | From baseline (week 0) to end of treatment (week 52) | 
| Change in ADC (apparent diffusion coefficient) (cortex) (MRI) | ratio | From baseline (week 0) to end of treatment (week 52) | 
| Change in ADC (medulla) (MRI) | ratio | From baseline (week 0) to end of treatment (week 52 | 
| Change in mean RARI (renal artery resistive index ) (MRI) | ratio | From baseline (week 0) to end of treatment (week 52) | 
| Change in mean arterial flow (MRI) | ratio | From baseline (week 0) to end of treatment (week 52) | 
| Change in natriuresis (urinary sodium excretion) (urinalysis) | mmol/l | From baseline (week 0) to end of treatment (week 52) | 
| Change in albumin excretion rate (urinalysis) | mg/24 hours | From baseline (week 0) to end of treatment (week 52) | 
| Change in kidney function (creatinine clearance) (urinalysis | ml/min/1.73 m^2 | From baseline (week 0) to end of treatment (week 52 |