A physician-initiated double-blind, randomised, placebo-controlled, phase 2 study evaluating the efficacy and safety of inhibition of NADPH oxidase with the first-in-class Nox-1/4 inhibitor, GKT137831, in adults with type 1 diabetes and persistently elevated urinary albumin excretion: Protocol and statistical considerations
Introduction
Diabetic kidney disease affects 14–31% of people with type 1 diabetes, causing microalbuminuria, macroalbuminuria, and/or decreased glomerular filtration rate [1]. Current management focuses on improved glycemic control, blood pressure and lipid control, and renin angiotensin system (RAS) blockade. However, the cumulative incidence of end stage renal disease (ESRD) was still 7.8% at 30 years after diagnosis of diabetes in the Finnish Diabetic Nephropathy [FinnDiane] Study), conducted between 1997 and 2006. Chronic kidney disease is associated with significantly increased all-cause mortality and incident cardiovascular disease in type 1 diabetes [2]. Therefore, novel treatment strategies are needed.
Oxidative stress caused by chronic hyperglycemia is a critical factor in the initiation and progression of diabetic kidney disease [3,4]. Reactive oxygen species (ROS) damage the glomerular epithelium, podocyte, mesangial cell and tubule [5]. The major source of renal ROS is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox), activated by hyperglycemia, advanced glycation end products, angiotensin II, cytokines and growth factors. Seven isoforms of Nox have been described in mammals. Each of these isoforms comprises a core catalytic subunit — the so-called NADPH oxidase (NOX) and dual oxidase (DUOX) subunits — and up to five regulatory subunits. Some NADPH oxidase isoforms also require a small GTPase for their activation. Each NADPH oxidase isoform may be defined by the nature of its core catalytic subunit (NOX1–NOX5, DUOX1 or DUOX2) as well as its suite of regulatory subunits.
Several isoforms, Nox-1, Nox-2, Nox-4 and Nox-5, are found in the kidney and blood vessels. Genetic deletion or pharmacologic inhibition of Nox-4 in diabetic mice attenuated albuminuria, extracellular matrix accumulation, fibrosis and renal inflammation [6,7]. Genetic deletion of Nox-1 reduced atherogenic changes but did not affect diabetic renal damage [8]. Therefore, homolog-specific inhibition of Nox-4 (for renal protection) and Nox-1 (for vascular protection) but not Nox-2 (required for immune protection) is a promising adjunct therapy for diabetes complications.
GKT137831 (also called setanaxib) is a small-molecule, dual Nox-4/Nox-1 inhibitor developed by Genkyotex (Saint-Julien- en-Genevois, France). Pre-clinical studies in mouse models of diabetes showed renal protection [6,9,10] even in established kidney and macrovascular disease [11]. A randomized, placebo-controlled Phase 2 trial in 136 people with type 2 diabetes and advanced kidney disease with macroalbuminuria [Clinicaltrials.gov reference NCT02010242] [12] treated 68 participants with GKT-137831 for 12 weeks, starting with 100 mg BID for 6 weeks and increasing to 200 mg BID for 6 weeks. There was no effect on the primary endpoint of albuminuria (personal communication). The geometric mean value for albuminuria with GKT137831 treatment was 705.7 mg/g at baseline and 774.2 mg/g at Week 12 (ratio 1.09), and for placebo treatment was 696.3 mg/g at baseline and 701.4 mg/g at Week 12 (ratio 1.04) in the ITT population. There was no effect on eGFR. GKT137831 had statistically significant beneficial effects on secondary efficacy endpoints of inflammation and liver injury with an excellent safety profile. The mean gamma-glutamyl transferase (GGT) value at end of treatment for in the GKT137831 group was 31.5 U/L and for placebo 34.3 U/L (p = .034). hs-CRP at end of treatment for the GKT137831 group was 2.06 mg/L compared to 3.30 mg/L for placebo (p = .022). The lack of effect on renal endpoints may have been due to the lower dose used in the first half of the study, short treatment duration, and/or treatment in people with advanced kidney disease.
The results of the trial in type 2 diabetic kidney disease cannot be extrapolated to the setting of type 1 diabetes, because other factors in type 2 diabetic kidney disease, such as hypertension and insulin resistance, make it more clinically heterogeneous. Therefore, a trial with longer treatment duration, higher GKT137831 dosage and a population with less advanced disease (microalbuminuria or macroalbuminuria, eGFR at least 40 ml/min/1.73 m2) has been designed.
This paper describes the protocol and proposed statistical analysis for a Phase 2 clinical trial that is the first to investigate the effect of GKT137831 on urinary albumin excretion in people with type 1 diabetes. This study is registered on the Australian and New Zealand Clinical Trial Registry (ACTRN12617001187336).
Section snippets
Study design
This is a Phase 2, double-blind, placebo-controlled, randomized study occurring at multiple sites globally, which is conducted in adults with type 1 diabetes and persistent albuminuria (as detailed in Table 2). The study plans to randomize 142 participants; to achieve this number of randomizations, up to 284 people may need to be screened. The study will evaluate the efficacy and safety of GKT137831 (400 mg/twice a day) over 48 weeks of treatment, with the primary endpoint at 48 weeks. The
Eligibility
To be eligible for the study, participants with type 1 diabetes will need to have persistent albuminuria, with documented abnormal UACRs in the preceding 24 months before enrolment in the trial. Participants will already be receiving standard of care therapy for albuminuria, and have well-controlled blood pressure and HbA1c. The occurrence within 13 weeks before screening of recent changes in medications that may alter albumin excretion or eGFR, or certain procedures that may potentially affect
Study assessments
The schedule of events for study assessments is shown in Table 4.
Efficacy evaluations
These are shown in Table 1.
Safety evaluations
The safety analyses will include the measurement of AEs, clinical laboratory tests, vital signs, physical examination findings and ECG. The clinical laboratory tests will include kidney and liver function tests, hematology, thyroid function tests; fasting plasma glucose (FPG), lipid profile, pregnancy tests and urine albumin to creatinine ratio.
Statistical evaluation
The primary efficacy endpoint is the difference between the mean UACR of each arm at the end of the treatment period of
Discussion
This multi-center, randomized, placebo-controlled, parallel arm clinical trial will add valuable information on the efficacy of Nox-1 and Nox-4 inhibition by GKT137831, in treating albuminuric kidney disease in type 1 diabetes. It builds on considerable pre-clinical data showing the fundamental importance of Nox-1 and Nox-4 in the development of kidney disease, pre-clinical proof of principle data showing functional and morphologic benefit of treatment with GKT137831 and safety data from
Funding
This study is an investigator-initiated trial funded by the Juvenile Diabetes Research Fund (JDRF) Australia, the recipient of the Australian Research Council Special Research Initiative in Type 1 Juvenile Diabetes, and by the Baker Heart and Diabetes Institute. Study drug is provided by Genkyotex S.A. (France). The Sponsor is the Baker Heart and Diabetes Institute and the study was designed by the members of the steering committee at the Institute and Monash University.
Disclosures/conflicts of Interest
KJD received previous small research grants from Genkyotex. MD has served on advisory boards and received honoraria from Eli Lilly and Company, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Sanofi, Bristol-Myers, Novartis, Otsuka and Abbot. GW is Editor in Chief of Obesity Research and Clinical Practice; he has served as International Advisor for Clinical Key (Elsevier) and is the Independent Chair of the Weight Management Council of Australia. He has had research support from Weight Watchers
Acknowledgements
The authors thank the participants, the study coordinators, clinical research associates from Mobius Medical Pty Ltd. for clinical trial monitoring, and the staff at PCI Pharma Services.
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