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Feasibility of Aggressive Albuminuria Reduction in Biopsy-Proven Diabetic Nephropathy - A Pilot Study (WP3)

Primary Purpose

Diabetic Kidney Disease

Status
Recruiting
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
ACEi / ARB, SGLT2i, finerenone, semaglutide, pentoxifylline, hydrochlorthiazide, baricitinib
Sponsored by
Iain Bressendorff
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diabetic Kidney Disease

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Age ≥ 18 years Diagnosis of diabetes mellitus type 2 (American Diabetes Association / European Association for the Study of Diabetes (ADA/EASD) definition)10 Biopsy-proven diabetic nephropathy UACR ≥ 2,000 mg/g or UACR ≥ 1,500 mg/g if treated with sodium-glucose cotransporter 2 inhibitor (SGLT2i) Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 Negative pregnancy test and use of highly effective and safe contraception Able to give informed consent. Exclusion Criteria: Kidney transplant recipient Findings on kidney biopsy suggestive of other or concomitant glomerulonephritis (findings associated with hypertensive nephropathy are not exclusion criteria). Plasma potassium at baseline > 5.2 mmol/L. Active malignancy (basal or squamous cell skin carcinoma, localised prostate cancer, and cancer with no signs of reoccurrence after 5 years are exempt from this). Systolic heart failure with NYHA class III-IV. Liver failure classified as Child-Pugh C. Primary hyperaldosteronism. Previous cerebral or retinal haemorrhage. Biliary obstructive disorders. Acute myocardial infarction within the last three months. Severe cardiac arrhythmias. Clinically active gout. Plasma sodium at baseline < 135 mmol/L. Other diseases or conditions, which, in the opinion of the site investigator, would prevent participation in or completion of the trial. Treatment with potent CYP3A4 inhibitors. Participation in other interventional trials. Allergy towards one of more of the drugs to be used during the trial

Sites / Locations

  • Department of Nephrology, Herlev and Gentofte HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Standard of Care

Albuminuria-reduction protocol

Arm Description

Maximally tolerated dose of ACEi or ARB (but not both), SGLT2i, and finerenone. Blood pressure target <130/80 mm Hg

Maximally tolerated dose of ACEi or ARB (but not both), SGLT2i, and finerenone. Thereafter addition of semaglutide, pentoxifylline, hydrochlorothiazide, and baricitinib. Blood pressure target <130/80 mm Hg, but if still UACR >300 further reduction in blood pressure will be attempted as tolerated.

Outcomes

Primary Outcome Measures

urine albumin/creatinin-ratio (UACR) reduction to less than 50% of baseline
number of subjects achieving this endpoint

Secondary Outcome Measures

UACR reduction to less than 70% of baseline
number of subjects achieving this endpoint
UACR less than 300
number of subjects achieving this endpoint
difference in UACR
between-groups difference in UACR
difference in UACR
between-groups difference in UACR
difference in eGFR
between-groups difference in eGFR
difference in eGFR
between-groups difference in eGFR
difference in blood pressure
between-groups difference in blood pressure
difference in blood pressure
between-groups difference in blood pressure
incidence of plasma potassium >5.5 mmol/L
number of subjects achieving this endpoint
incidence of plasma potassium >6.0 mmol/L
number of subjects achieving this endpoint
incidence of symptomatic hypotension
number of subjects achieving this endpoint

Full Information

First Posted
May 31, 2023
Last Updated
May 31, 2023
Sponsor
Iain Bressendorff
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1. Study Identification

Unique Protocol Identification Number
NCT05897372
Brief Title
Feasibility of Aggressive Albuminuria Reduction in Biopsy-Proven Diabetic Nephropathy - A Pilot Study
Acronym
WP3
Official Title
Feasibility of Aggressive Albuminuria Reduction in Biopsy-Proven Diabetic Nephropathy - A Pilot Study
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 1, 2023 (Anticipated)
Primary Completion Date
June 1, 2025 (Anticipated)
Study Completion Date
June 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Iain Bressendorff

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this trial is to investigate the feasibility and safety of implementing a protocol-based treatment aggressively targeting albuminuria in subjects with biopsy-proven diabetic nephropathy and severely elevated albuminuria. If this approach is feasible, the results of the trial will inform the design of a large-scale randomized clinical trial to evaluate the effect of this treatment on hard kidney endpoints (initiation of dialysis, kidney transplantation, and death from kidney failure) in subjects with biopsy-proven diabetic nephropathy and severely elevated albuminuria.
Detailed Description
Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD) worldwide and declining kidney function is associated with a graded increase in the risk of death or hospitalization. Thus, prevention of kidney disease progression is of vital importance to prevent excess morbidity and mortality among people with DKD. Increasing levels of albuminuria in patients with DKD are associated with a graded increase in the risk of developing ESKD and among patients with nephrotic-range albuminuria (i.e. > 2.000 mg/day) progressive decline in kidney function is particularly rapid. The currently available drugs which have demonstrated delayed progression to ESKD in DKD (captopril, losartan and irbesartan, canagliflozin, dapagliflozin, empagliflozin, and finerenone) all reduce albuminuria independently of blood pressure reductions, but it has long been debated whether reductions in albuminuria by itself reflects a reduction in the risk of ESKD or whether this is simply a by-product of treatment. Whether interventions targeting reductions in albuminuria reduce the incidence of ESKD has not been formally tested in a randomized controlled trial of hard kidney endpoints (e.g. initiation of dialysis, kidney transplantation or death from kidney disease). We wish to conduct a randomized controlled trial in which we will test whether an aggressive treatment strategy of lowering albuminuria reduces the incidence of hard kidney endpoints compared to standard-of-care among patients with nephrotic-range albuminuria and very high risk of progression to ESKD. However, prior to conducting such a trial it is necessary first to test whether it is even possible to sufficiently lower albuminuria by these means. Therefore, we wish to first conduct a pilot trial to investigate the feasibility of such an approach. Participants will be randomized 1:1 to standard-of-care or an albuminuria-reduction protocol. In the albuminuria-reduction protocol, subjects will be treated with various drugs that have all been shown to reduce albuminuria in DKD (although not all have been shown to reduce hard kidney outcomes). At each monthly study visit, drugs will be added or withdrawn in an attempt to maximally reduce albuminuria. Drugs that reduce albuminuria by <10% since the last study visit will be discontinued. Drugs that successfully reduce albuminuria by >10% will be continued and further drugs will be added. After 9 months subjects will discontinue protocol drugs and resume their previous medical care.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetic Kidney Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Randomized, controlled, open-label, parallel-group, clinical trial.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Standard of Care
Arm Type
Active Comparator
Arm Description
Maximally tolerated dose of ACEi or ARB (but not both), SGLT2i, and finerenone. Blood pressure target <130/80 mm Hg
Arm Title
Albuminuria-reduction protocol
Arm Type
Experimental
Arm Description
Maximally tolerated dose of ACEi or ARB (but not both), SGLT2i, and finerenone. Thereafter addition of semaglutide, pentoxifylline, hydrochlorothiazide, and baricitinib. Blood pressure target <130/80 mm Hg, but if still UACR >300 further reduction in blood pressure will be attempted as tolerated.
Intervention Type
Drug
Intervention Name(s)
ACEi / ARB, SGLT2i, finerenone, semaglutide, pentoxifylline, hydrochlorthiazide, baricitinib
Intervention Description
Standard of care for diabetic kidney disease.
Primary Outcome Measure Information:
Title
urine albumin/creatinin-ratio (UACR) reduction to less than 50% of baseline
Description
number of subjects achieving this endpoint
Time Frame
after 9 months of treatment
Secondary Outcome Measure Information:
Title
UACR reduction to less than 70% of baseline
Description
number of subjects achieving this endpoint
Time Frame
after 9 months of treatment
Title
UACR less than 300
Description
number of subjects achieving this endpoint
Time Frame
after 9 months of treatment
Title
difference in UACR
Description
between-groups difference in UACR
Time Frame
after 9 months of treatment
Title
difference in UACR
Description
between-groups difference in UACR
Time Frame
after 10 months of treatment (1 month off study drugs)
Title
difference in eGFR
Description
between-groups difference in eGFR
Time Frame
after 9 months of treatment
Title
difference in eGFR
Description
between-groups difference in eGFR
Time Frame
after 10 months of treatment (1 month off study drugs)
Title
difference in blood pressure
Description
between-groups difference in blood pressure
Time Frame
after 9 months of treatment
Title
difference in blood pressure
Description
between-groups difference in blood pressure
Time Frame
after 10 months of treatment (1 month off study drugs)
Title
incidence of plasma potassium >5.5 mmol/L
Description
number of subjects achieving this endpoint
Time Frame
after 9 months of treatment
Title
incidence of plasma potassium >6.0 mmol/L
Description
number of subjects achieving this endpoint
Time Frame
after 9 months of treatment
Title
incidence of symptomatic hypotension
Description
number of subjects achieving this endpoint
Time Frame
after 9 months of treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥ 18 years Diagnosis of diabetes mellitus type 2 (American Diabetes Association / European Association for the Study of Diabetes (ADA/EASD) definition)10 Biopsy-proven diabetic nephropathy UACR ≥ 2,000 mg/g or UACR ≥ 1,500 mg/g if treated with sodium-glucose cotransporter 2 inhibitor (SGLT2i) Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 Negative pregnancy test and use of highly effective and safe contraception Able to give informed consent. Exclusion Criteria: Kidney transplant recipient Findings on kidney biopsy suggestive of other or concomitant glomerulonephritis (findings associated with hypertensive nephropathy are not exclusion criteria). Plasma potassium at baseline > 5.2 mmol/L. Active malignancy (basal or squamous cell skin carcinoma, localised prostate cancer, and cancer with no signs of reoccurrence after 5 years are exempt from this). Systolic heart failure with NYHA class III-IV. Liver failure classified as Child-Pugh C. Primary hyperaldosteronism. Previous cerebral or retinal haemorrhage. Biliary obstructive disorders. Acute myocardial infarction within the last three months. Severe cardiac arrhythmias. Clinically active gout. Plasma sodium at baseline < 135 mmol/L. Other diseases or conditions, which, in the opinion of the site investigator, would prevent participation in or completion of the trial. Treatment with potent CYP3A4 inhibitors. Participation in other interventional trials. Allergy towards one of more of the drugs to be used during the trial
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Iain Bressendorff, MD PhD
Phone
+4524277139
Email
iain@bressendorff.com
First Name & Middle Initial & Last Name or Official Title & Degree
Ditte Hansen, MD PhD
Phone
+4538682056
Email
ditte.hansen.04@regionh.dk
Facility Information:
Facility Name
Department of Nephrology, Herlev and Gentofte Hospital
City
Herlev
ZIP/Postal Code
2730
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Iain Bressendorff, MD PhD
Phone
+4524277139
Email
iain@bressendorff.com

12. IPD Sharing Statement

Plan to Share IPD
No

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Feasibility of Aggressive Albuminuria Reduction in Biopsy-Proven Diabetic Nephropathy - A Pilot Study

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