Nox 1 and 4 inhibition in type 1 diabetic kidney disease

• Register: ANZCTR
• Last refreshed on: 13 March 2023
• Main ID: ACTRN12617001187336
• Date of registration: 14/08/2017
• Prospective Registration: Yes
• Primary sponsor: Baker Heart and Diabetes Institute
• Public title: Nox 1 and 4 inhibition in type 1 diabetic kidney disease
• Scientific title: 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.
• Date of first enrolment: 12/12/2017
• Target sample size: 92
• Recruitment status: Stopped early
• URL: https://anzctr.org.au/ACTRN12617001187336.aspx
• Study type: Interventional
• Study design: Purpose: Treatment; Allocation: Randomised controlled trial; Masking: Blinded (masking used);Assignment: Parallel;Type of endpoint: Efficacy;
• Phase: Phase 2

Countries of recruitment

Australia, New Zealand

Contacts

• Name: Prof Jonathan Shaw

• Name: Prof Mark Cooper

Key inclusion & exclusion criteria

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

Age minimum: 18 Years
Age maximum: 70 Years
Gender: Both males and females

Health Condition(s) or Problem(s) studied

Renal and Urogenital - Kidney disease

diabetic kidney disease;type 1 diabetes;
diabetic kidney disease
type 1 diabetes

Metabolic and Endocrine - Diabetes

Intervention(s)

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.

Primary Outcome(s)

The primary efficacy endpoint for this study is the difference between the two treatment arms in mean urine albumin to creatinine ratio (UACR) at the end of the treatment period of 48 weeks, adjusted for baseline UACR.
Baseline UACR is defined as the geometric mean of 4 UACRs, which consist of the 2 consecutive daily first void UACR values at Visit 2 (2 weeks before randomisation) and the 2 consecutive daily first void UACR values at Visit 3 (randomisation).
UACR at the end of the treatment period of 48 weeks is defined as the geometric mean of 4 UACRS, which consist of the 2 consecutive daily first void UACR values at Visit 8 (46 weeks of treatment) and the 2 consecutive daily first void UACR values at Visit 9 (48 weeks of treatment).

[48 weeks]

Secondary Outcome(s)

The differences between the two treatment arms in mean diastolic blood pressure, adjusted for baseline values.[24 and 48 weeks]

The differences between the two treatment arms in mean diastolic diastolic blood pressure, adjusted for baseline values.[24 and 48 weeks]

The differences between the two treatment arms in mean weight, adjusted for baseline values.[24 and 48 weeks]

To assess the effects of add-on therapy with GKT137831 400 mg twice a day compared to placebo on thyroid function tests (thyroid stimulating hormone).[48 weeks]

The difference between the two treatment arms in mean eGFR at 24 weeks of treatment, adjusted for baseline eGFR. The eGFR at 24 weeks is the value of the sample taken at Visit 6. eGFR is calculated from serum creatinine. [24 weeks]

To assess the effects of add-on therapy with GKT137831 400 mg twice a day compared to placebo on full blood examination (measured on blood sample), 29 participants had already been randomised. [24 and 48 weeks]

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. [For the study visits post intervention commencement, at 4, 12, 24, 36, 46, 48 and 52 weeks.]

Inflammatory markers: assessed in a laboratory by measurement of fibrinogen, high sensitivity C reactive protein and interleukin-6 in plasma samples (fibrinogen) and serum samples (for the other two markers).[24 and 48 weeks]

Predose plasma concentrations of GKT137831 will be assessed.[4, 12 and 36 weeks]

Predose plasma concentrations of the main phase 1 metabolite, GKT138184, will be assessed.[4, 12 and 36 weeks]

The difference between the two treatment arms in renal function measured by mean eGFR (estimated glomerular filtration rate) at 48 weeks of treatment, adjusted for baseline eGFR. Baseline eGFR is defined as the geometric mean of 2 eGFRs, which are the eGFR at Visit 2 and eGFR at Visit 3. The end of treatment eGFR at 48 weeks is defined as the geometric mean of 2 eGFRs, which are the eGFR at Visit 8 and the eGFR at Visit 9. eGFR is calculated from serum creatinine measured in the biochemistry laboratory.[48 weeks]

To assess the effects of add-on therapy with GKT137831 400 mg twice a day compared to placebo on HbA1c (glycated haemoglobin) -measured by blood sample.[24 and 48 weeks]

Update To assess the effects of add-on therapy with GKT137831 400 mg twice a day compared to placebo on fasting lipid tests (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) measured by blood sample. [24 and 48 weeks]

Secondary outcome: The difference between the two treatment arms in mean UACR at 24 weeks of treatment, adjusted for baseline UACR. The UACR at 24 weeks of treatment is defined as the geometric mean of the 2 consecutive daily first void UACR values at Visit 6 (24 weeks). UACR will be assessed by performing biochemistry test on the urine samples. [24 weeks (Visit 6)]

To assess the effects of add-on therapy with GKT137831 400 mg twice a day compared to placebo on fasting glucose (measured by blood sample).[24 and 48 weeks]

Update To assess the effects of add-on therapy with GKT137831 400 mg twice a day compared to placebo on liver function tests (bilirubin, alkaline phosphatase, gamma glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin) measured by blood sample.[24 and 48 weeks]

The difference between the two treatment arms in mean QTc (QT interval, corrected -measured by electrocardiogram), adjusted for baseline values.[24 and 48 weeks]

The differences between the two treatment arms in mean heart rate, adjusted for baseline values.[24 and 48 weeks]

The differences between the two treatment arms in mean systolic blood pressure, adjusted for baseline values.[24 and 48 weeks]

Secondary ID(s)

GSN000241

Protocol number: T1DGKT137831

Source(s) of Monetary Support

Baker Heart and Diabetes Institute

Juvenile Diabetes Research Foundation (JDRF). Australian Type 1 Diabetes Clinical Research Network research grant

Genkyotex S.A.

Ethics review

Status: Approved
Approval date: 23/06/2017
Contact:

Alfred Hospital Ethics Committee

Status: Not approved
Approval date:
Contact:

South Metropolitan Health Service Human Research Ethics Committee

Results

• Results available: Yes
• Date Posted: 03/03/2023
• Date Completed: 22/11/2022