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

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.

Study Overview

• Status: Terminated
• Conditions: Diabetic Kidney Disease
• Intervention / Treatment: Drug: ACEi / ARB, SGLT2i, finerenone, semaglutide, pentoxifylline, hydrochlorthiazide, baricitinib

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.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Herlev, Denmark, 2730
    • Department of Nephrology, Herlev and Gentofte Hospital

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of Care; Maximally tolerated dose of ACEi or ARB (but not both), SGLT2i, and finerenone. Blood pressure target <130/80 mm Hg	Drug: ACEi / ARB, SGLT2i, finerenone, semaglutide, pentoxifylline, hydrochlorthiazide, baricitinib; Standard of care for diabetic kidney disease.
Experimental: Albuminuria-reduction protocol; 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.	Drug: ACEi / ARB, SGLT2i, finerenone, semaglutide, pentoxifylline, hydrochlorthiazide, baricitinib; Standard of care for diabetic kidney disease.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
urine albumin/creatinin-ratio (UACR) reduction to less than 50% of baseline	number of subjects achieving this endpoint	after 9 months of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
UACR reduction to less than 70% of baseline	number of subjects achieving this endpoint	after 9 months of treatment
UACR less than 300	number of subjects achieving this endpoint	after 9 months of treatment
difference in UACR	between-groups difference in UACR	after 9 months of treatment
difference in UACR	between-groups difference in UACR	after 10 months of treatment (1 month off study drugs)
difference in eGFR	between-groups difference in eGFR	after 9 months of treatment
difference in eGFR	between-groups difference in eGFR	after 10 months of treatment (1 month off study drugs)
incidence of plasma potassium >5.5 mmol/L	number of subjects achieving this endpoint	after 9 months of treatment
incidence of plasma potassium >6.0 mmol/L	number of subjects achieving this endpoint	after 9 months of treatment
incidence of symptomatic hypotension	number of subjects achieving this endpoint	after 9 months of treatment
difference in systolic and diastolic blood pressure	between-groups difference in blood pressure	after 9 months of treatment
difference in systolic and diastolic blood pressure	between-groups difference in blood pressure	after 10 months of treatment (1 month off study drugs)

Collaborators and Investigators

• Sponsor: Iain Bressendorff
• Investigators: Principal Investigator: Iain Bressendorff, MD PhD, Herlev and Gentofte Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2023
• Primary Completion (Actual): September 23, 2024
• Study Completion (Actual): September 23, 2024

Study Registration Dates

• First Submitted: May 31, 2023
• First Submitted That Met QC Criteria: May 31, 2023
• First Posted (Actual): June 9, 2023

Study Record Updates

• Last Update Posted (Actual): September 25, 2024
• Last Update Submitted That Met QC Criteria: September 23, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Urination Disorders; Proteinuria; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Diabetic Nephropathies; Albuminuria; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Glucagon-Like Peptide-1 Receptor Agonists; Pentoxifylline; Semaglutide
• Other Study ID Numbers: PRIMETIME - WP3

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