None listed
Conditions
Brief summary
This is a multicentre, phase 2, randomised, double-blind, placebo-controlled clinical trial with two parallel arms, which will test the effect of GKT137831 200 mg twice a day compared to placebo on urine albumin to creatinine ratio, in adults with type 1 diabetes and persistent albuminuria despite optimal preceding standard of care treatment. We hope to get 92 randomised in order to get 80 people complete treatment. The treatment period is for 48 weeks with total study duration for the participant of up to 56 weeks. There will be 10 study visits. Analyses will include urine albumin: creatinine ratio, HbA1c, renal and liver function, full blood examination, thyroid stimulating hormone, fasting glucose, fasting lipids, pregnancy test if applicable.
Interventions
GKT137831, 400 mg twice a day taken as oral capsules for 48 weeks, added to standard of care treatment for albuminuric diabetic kidney disease. Adherence to the intervention will be monitored by drug capsule return.
Sponsors
Baker Heart and Diabetes Institute
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Capable of understanding the content of and able voluntarily to provide a personally signed and dated written informed consent form. 2. Stated willingness to comply with all study procedures and availability for the duration of the study. 3. Male or female, aged 18-70 years inclusive. 4. Clinical diagnosis of type 1 diabetes, defined as at least 2 out of 3 of the following: (i) age of onset < 40 years, (ii) insulin commenced within 1 year of the diagnosis of diabetes, (iii) positive autoantibodies for at least 1 of the antibodies associated with type 1 diabetes (islet cell antibody [ICA], insulin autoantibody [IAA], tyrosine phosphatase–like insulinoma antigen-2 autoantibody [IA-2A], zinc transporter 8 autoantibody (ZnT8 A) and glutamic acid decarboxylase autoantibody [GADA]). 5. Established albuminuria, defined as an urine albumin to creatinine ratio (UACR) greater than or equal to 2.5 mg/mmol in men or greater than or equal to 3.5 mg/mmol in women, with (a) the most recent UACR to have been within the albuminuria range and collected within the 12 months before Visit 1, AND (b) at least one other UACR within the albuminuria range in the last 24 months before Visit 1, AND (c) with not more than 1 normal UACR (i.e. <2.5 mg/mmol in men or <3.5 mg/mmol in women) in the 24 months before Visit 1, AND (d) the geometric mean of the 2 UACR tests collected at Visit 1 is in the albuminuria range, greater or equal to 2.5 mg/mmol in men or greater or equal to 3.5 mg/mmol in women. 6. eGFR greater or equal to 40 mL/min/1.73 m2, as calculated by the CKD-EPI creat formula, at Visit 1. 7. Participants must be taking either ACEI or ARB at a constant dose for at least 13 weeks prior to Visit 1, where the dose of the ACEI or the ARB is considered appropriate for that patient (up to maximum daily dose approved by the TGA) and it is anticipated that the same dose can and will be maintained throughout the course of the study. The only exception is if the participant has a documented intolerance to RAS blockade, such that neither an ACEI nor ARB are used or intended to be used for the duration of the study. The nature of the intolerance (e.g. hyperkalaemia, hypotension) must be documented by the Investigator in the study record at Visit 1. Combination therapy using an ACEI and an ARB is not permitted. 8. Participants taking any blood pressure-lowering medications in addition to an ACEI or ARB, including diuretics, must be on a stable dose for at least 13 weeks prior to Visit 1. 9. Ability to take oral medication and be willing to adhere to the medication regimen. 10. Willing to practice highly effective methods of birth control (both males who have partners of childbearing potential and females of childbearing potential) during the screening period, while taking investigational product and for at least 90 days after the last dose of investigational product is ingested. Women of childbearing potential are female participants who are not surgically sterile (no history of bilateral tubal ligation, hysterectomy, or bilateral salpingo-oophorectomy), and are not postmenopausal for at least 1 year. Furthermore, male study participants must also not donate sperm from day of randomisation until 90 days after the last dose of investigational product.
Exclusion criteria
1. History of type 2 diabetes. 2. HbA1c at Visit 1 greater or equal to 10.0% (greater or equal to 86 mmol/mol). 3. Chronic kidney disease due to a documented history of non-diabetic kidney disease(s), except for hypertensive nephropathy, which is acceptable. Therefore, the chronic kidney disease must be due to diabetic kidney disease, with or without hypertensive kidney disease. a. Diagnostic or interventional procedure requiring a contrast agent within 4 weeks of the first screening visit. b. Untreated urinary tract infection at Visit 1 that would impact urinary protein levels. c. History of renal transplant or other solid organ transplant, or planned renal transplant or other solid organ transplant during the study. d. A history of acute renal dialysis or acute kidney injury (defined according to the Kidney Disease: Improving Global Outcomes [KDIGO] definition) within 13 weeks of Visit 1. 4. Body mass index (BMI) <18.5 kg/m2 or >40 kg/m2. 5. eGFR <40 ml/min/1.73m2, as calculated by the CKD-EPI creat formula. 6. Alteration in anti-hypertensive therapy within 13 weeks prior to Visit 1, including change in dosing with ACEI or ARB. 7. Women who are lactating, pregnant, or intend to become pregnant during the course of the study. 8. Participants with clinically significant liver disease or elevated liver enzymes, defined as alkaline phosphatase or transaminase (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) levels >3 × the upper limit of normal (ULN) measured at Visit 1 or bilirubin >1.5 x the ULN measured at Visit 1. 9. Inadequately controlled arterial blood pressure, defined as SBP >160 mmHg at Visit 1 or DBP > 95 mm Hg at Visit 1. 10. Current history of thyroid disorder requiring thyroid hormone replacement therapy, unless the dose of thyroid hormone replacement has been stable for at least 4 weeks prior to Visit 1 and the thyroid stimulating hormone (TSH) value is not greater than the ULN at Visit 2. 11. History of active cardiovascular disease defined as the occurrence of the following events or conditions within the 13 weeks preceding Visit 1: acute myocardial infarction; unstable angina pectoris; stroke, including a transient ischemic attack; a coronary revascularisation 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 Fridericia interval >450 milliseconds for males and >470 milliseconds for females; second or third degree AV block not successfully treated with a pacemaker. Fridericia’s correction QTc = QT/RR0.33. 14. A history of bone marrow disorder, including aplastic anaemia, or marked anaemia at Visit 1 defined as haemoglobin < 100 g/L. 15. Participants with a history of treatment for neoplastic disease within 5 years prior to Visit 1. The exceptions allowed are adequately treated basal or squamous cell carcinoma of the skin, adequately treated in situ carcinomas of the cervix, prostate, ductal breast, or superficial bladder cancer stage 0. 16. Current history of drug or alcohol abuse, as assessed by the site Investigator. 17. The occurrence of any acute infection requiring systemic antibiotic therapy within the 2 weeks prior to Visit 1, or known infection with hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection. 18. Use of the following medications within 4 weeks of Visit 1: direct renin inhibitors, endothelin receptor antagonists. 19. Participants anticipated to require systemic immunosuppression therapy for >2 weeks during the study or a past history of systemic immunosuppression for more than 2 weeks, cumulatively, within the 13 weeks prior to Visit 1. Inhaled steroids are not considered to be systemic immunosuppression. 20. Administration of any investigational product within 30 days or within 5 half-lives of the investigational agent (whichever is longer) of Visit 1. 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.
Outcome results
None listed