Professor Jonathan Shaw from the Baker IDI Heart and Diabetes Institute and collaborators from across Australia are investigating the ability of a new type of antioxidant drug to improve kidney function in people with type 1 diabetes.

Even with careful blood glucose management, many people with type 1 diabetes develop kidney complications. Current treatment options for diabetic kidney disease can slow but not stop its progression. There is an urgent need to develop new treatments to arrest, reverse and prevent the development of kidney complications. 

In people with type 1 diabetes the damaging effects of high blood glucose levels are caused in part by increased generation of free radicals, or reactive oxygen species (ROS). As the name suggests, ROS quickly and indiscriminately react with almost anything they come in contact with including DNA, proteins, and other vital cell structures causing widespread damage to the kidneys and other organs. The damage caused by ROS is called oxidative stress. 

This clinical trial will be testing an agent that blocks a key component of the ROS pathway in T1D patients with early-stage kidney disease. Prof Shaw and his team anticipate that blocking production of ROS will reduce oxidative stress in the kidney – resulting in improvements in kidney function. Preliminary studies of this compound using animal models of type 1 diabetes have been extremely promising, and have shown that it is safe. 

The success of this compound in human clinical trials would be a major breakthrough for the treatment and prevention of kidney complications in type 1 diabetes.

More information about the project will be released when available.

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Full Detail About This Clinical Trial

Technical Summary

All strategies for the prevention of complications associated with diabetes rely on the premise that the deleterious effects of high glucose levels and an enhanced metabolic flux are mediated by the generation of toxic metabolites. Of these, reactive oxygen species (ROS) are among the most important. Numerous studies have demonstrated that altered levels of ROS are associated with adverse clinical outcomes in type 1 diabetes. Experimental studies have demonstrated that strategies to reduce the production of reactive intermediates or to increase defence against them, may prevent end-organ damage.

This study will test a first-in-class selective inhibitor of NADPH oxidase, GKT137831, for reducing oxidative stress in the kidney through inhibition of Nox1/4 as a means to reduce albuminuria and attenuate progressive nephropathy in type 1 diabetes. This study is based on pilot experimental data which have demonstrated the reno-protective, as well as retinoprotective and cardiovascular-protective potential for this strategy in experimental models of type 1 diabetes.

Trial Design

An investigator initiated double-blind, randomised, placebo-controlled phase IIa study evaluating oral administration of 200mg GKT137831 twice daily for 24 weeks in 138 adults with type 1 diabetes and elevated urinary albumin excretion.

Principal Investigator

Professor Jonathan Shaw

Funders

The Australian Type 1 Diabetes Clinical Research Network

Infrastructure support is provided through an NHMRC/JDRF Centre of Research Excellence Grant, as well as funding for students and training.

Locations

Victoria

  • Baker IDI Heart and Diabetes Institute
  • The Alfred Hospital
  • Monash Health
  • The Austin Hospital
  • St Vincent’s Hospital Melbourne
  • Royal Melbourne Hospital
  • Barwon Health
  • Western Health

 New South Wales

  • Royal North Shore Hospital
  • Royal Prince Alfred Hospital
  • Hunter Diabetes Centre

 Queensland

  • Royal Brisbane and Women's Hospital

South Australia

  • Royal Adelaide Hospital

Western Australia

  • Fremantle Hospital
Primary Endpoint

The change from baseline to the log-transformed geometric mean of the urine albumin/creatinine ratios (UACR) at weeks 16, 20 and 24 of treatment.

Secondary Endpoints

Safety and changes in key laboratory parameters including GFR, HbA1c, lipid and blood pressure.

Inclusion/Exclusion

Inclusion Criteria

    1. Adults aged 18-70 years with type 1 diabetes and HbA1C <10%
    2. Established albuminuria: UACR > 2.5 mg/mmol in men or >3.5 mg/mmol in women currently, and on two previous occasions consecutively.
    3. Systolic BP < 160 mm Hg, Diastolic BP < 95 mm Hg.
    4. An eGFR > 60 mL/min/1.73 m2, as calculated by the CKD-EPI creat formula.
    5. Taking an ACE inhibitor (ACEI) or an ARB at the same dose for at least 13 weeks prior to the first screening visit (Visit 1) or been intolerant to RAS blockade such that neither are used (or intended to be used).

Exclusion Criteria

    1. History of type 2 diabetes.
    2. A documented history of non-diabetic kidney disease(s) except for hypertensive nephropathy which is acceptable.
    3. Diagnostic or interventional procedure requiring a contrast agent within 4 weeks of the first screening visit.
    4. History of renal transplant or planned renal transplant during the study.
    5. A body mass index (BMI) <18.5 kg/m2 or >40 kg/m2.
    6. A positive pregnancy test or breast-feeding.
    7. Elevated liver enzymes (alkaline phosphatase or alanine aminotransferase [ALT]) >3 x the upper limit of normal (ULN), or bilirubin >1.5 x the ULN).
    8. Estimated GFR<40 ml/min/1.73m2, as calculated by the CKD-EPI formula.
    9. Alteration in anti-hypertensive therapy within 13 weeks prior to Visit 1, including change in dosing with ACEI or angiotensin receptor blocker (ARB).
    10. Current history of thyroid disorder requiring thyroid hormone replacement therapy, unless the dose of thyroid hormone(s) has been stable for at least 4 weeks prior to the first screening visit (Visit 1) and the thyroid stimulating hormone (TSH) value is not greater than the upper limit of the normal range at Visit 2.
    11. History of active cardiovascular disease defined as the occurrence of the following events or conditions within the 13 weeks preceding the first screening Visit 1: acute myocardial infarction; unstable angina pectoris; stroke, including a transient ischemic attack; a coronary revascularization procedure; congestive heart failure New York Health Association (NYHA) Class III or IV.
    12. A personal or family history of long QT syndrome.
    13. Evidence of any of the following cardiac conduction abnormalities during the screening period: A QTc interval >450 milliseconds for males and >470 milliseconds for females. A second or third degree AV block not successfully treated with a pacemaker.
    14. Participants with a history of treatment for neoplastic disease within 5 years to Visit 1. The exceptions allowed are adequately treated basal or squamous cell carcinoma of the skin, adequately treated in situ carcinomas of the cerix, prostate, ductal breast, or superficial bladder cancer stage 0.
    15. Current history of drug or alcohol abuse, as assessed by the Investigator.
    16. The occurrence of any acute infection requiring systemic antibiotic therapy within the 2 weeks prior to the first day of the study, or infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
    17. A history of bone marrow disorder including aplastic anaemia.
    18. Use of the following medications within 4 weeks of Visit 1: direct renin inhibitors, endothelin receptior antagonists. 
    19. Participants anticipated to require systemic immunosuppression therapy for >2weeks during the study or a past history of systemic immunosuppression for more than 2 weeks, cumlatively, with the 13 weeks prior to Visit 1. Inhaled steroids are not considered to be system to be systemic immuosuppression. 
    20. Administration of any investigational product within 30 days or within 5 half-lives of the investigational agent (whichever is longer) of the first day of the study.
    21. Any condition which, in the opinion of the Investigator, constitutes a risk or contraindication for the participation of the participant in the study, or that could interfere with the study objectives, conduct, or evaluation.  This includes participants unlikely to comply with the study protocol (e.g. an inability and unwillingness to participate in adequate training, an uncooperative attitude, inability to return for follow-up visits, or unlikelihood of completing the study).
    22. Persons employed by the Sponsor, CRO or Genkyotex.
    23. Persons who are Investigator site personnel directly affiliated with this study and/or their immediate families. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or adopted.
    24. Use of sodium glucose transporter protein 2 (SGLT2) inhibitors within 13 weeks of Visit 1 or potential use during the duration of the study.
Anticipated Outcomes

If the renoprotective response to GKT137831 is similar to what has been seen in preliminary experimental studies, it will represent a major breakthrough for the prevention and management of kidney disease in type 1 diabetes.

It is anticipated that positive results of this study will lead to larger and longer studies, most likely on an international scale, to validate findings and enhance potential registration of this drug in clinical practice. Given the common pathogenic pathways in diabetic complications, positive results may lead to this agent being explored in other key areas including retinopathy and neuropathy.

Start/End Date

2016- 2020

 

Last updated 6th September 2019