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Trial registered on ANZCTR


Registration number
ACTRN12617001187336
Ethics application status
Approved
Date submitted
8/08/2017
Date registered
14/08/2017
Date last updated
3/03/2023
Date data sharing statement initially provided
4/12/2018
Type of registration
Prospectively registered

Titles & IDs
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.
Secondary ID [1] 291592 0
Protocol number: T1DGKT137831
Secondary ID [2] 291593 0
GSN000241
Universal Trial Number (UTN)
U1111-1187-2609
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
type 1 diabetes 302708 0
diabetic kidney disease 302707 0
Condition category
Condition code
Renal and Urogenital 302224 302224 0 0
Kidney disease
Metabolic and Endocrine 302223 302223 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 297660 0
Treatment: Drugs
Comparator / control treatment
Placebo added to standard of care treatment for albuminuric diabetic kidney disease.
Control group
Placebo

Outcomes
Primary outcome [1] 301637 0
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).

Timepoint [1] 301637 0
48 weeks
Secondary outcome [1] 337754 0
The differences between the two treatment arms in mean heart rate, adjusted for baseline values.
Timepoint [1] 337754 0
24 and 48 weeks
Secondary outcome [2] 336985 0
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.
Timepoint [2] 336985 0
For the study visits post intervention commencement, at 4, 12, 24, 36, 46, 48 and 52 weeks.
Secondary outcome [3] 337750 0
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).
Timepoint [3] 337750 0
48 weeks
Secondary outcome [4] 333370 0
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.
Timepoint [4] 333370 0
24 weeks (Visit 6)
Secondary outcome [5] 336987 0
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).
Timepoint [5] 336987 0
24 and 48 weeks
Secondary outcome [6] 336986 0
Predose plasma concentrations of GKT137831 will be assessed.
Timepoint [6] 336986 0
4, 12 and 36 weeks
Secondary outcome [7] 337745 0
The differences between the two treatment arms in mean systolic blood pressure, adjusted for baseline values.
Timepoint [7] 337745 0
24 and 48 weeks
Secondary outcome [8] 337744 0
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.
Timepoint [8] 337744 0
24 weeks
Secondary outcome [9] 337749 0

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.
Timepoint [9] 337749 0
24 and 48 weeks
Secondary outcome [10] 337747 0
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.
Timepoint [10] 337747 0
24 and 48 weeks
Secondary outcome [11] 337753 0
The differences between the two treatment arms in mean diastolic diastolic blood pressure, adjusted for baseline values.
Timepoint [11] 337753 0
24 and 48 weeks
Secondary outcome [12] 337751 0
The difference between the two treatment arms in mean QTc (QT interval, corrected -measured by electrocardiogram), adjusted for baseline values.
Timepoint [12] 337751 0
24 and 48 weeks
Secondary outcome [13] 337752 0
The differences between the two treatment arms in mean diastolic blood pressure, adjusted for baseline values.
Timepoint [13] 337752 0
24 and 48 weeks
Secondary outcome [14] 337743 0
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.
Timepoint [14] 337743 0
48 weeks
Secondary outcome [15] 337758 0

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.
Timepoint [15] 337758 0
24 and 48 weeks
Secondary outcome [16] 337746 0
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).
Timepoint [16] 337746 0
24 and 48 weeks
Secondary outcome [17] 337755 0
The differences between the two treatment arms in mean weight, adjusted for baseline values.
Timepoint [17] 337755 0
24 and 48 weeks
Secondary outcome [18] 337756 0
Predose plasma concentrations of the main phase 1 metabolite, GKT138184, will be assessed.
Timepoint [18] 337756 0
4, 12 and 36 weeks
Secondary outcome [19] 337748 0
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.
Timepoint [19] 337748 0
24 and 48 weeks

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by IVRS/IWRS
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Stratified randomization. Randomisation will be stratified by UACR (females UACR less than or equal to 35, > 35 mg/mmol; males UACR less than or equal to 25, > 25 mg/mmol) and by study centre.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
The assumptions for the power calculations were: mean UACR of 13.56 mg/mmol for the control arm, difference between UACR means of the treatment arms of 3.56 mg/mmol/L (26%), SD of 7.5 mg/mmol, power of 80% with a 1 sided alpha of 0.05.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Other reasons/comments
Other reasons
The funding body JDRF would not continue paying for further recruitment.
Date of first participant enrolment
Anticipated
28/08/2017
Actual
12/12/2017
Date of last participant enrolment
Anticipated
Actual
12/10/2021
Date of last data collection
Anticipated
30/06/2022
Actual
22/11/2022
Sample size
Target
92
Accrual to date
Final
83
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 12637 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 12642 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [3] 12636 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [4] 12633 0
Baker Heart and Diabetes Institute - Melbourne
Recruitment hospital [5] 12635 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [6] 12644 0
Hunter Diabetes Centre - Merewether
Recruitment hospital [7] 12639 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [8] 12641 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [9] 12638 0
Sunshine Hospital - St Albans
Recruitment hospital [10] 12646 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 25060 0
3021 - St Albans
Recruitment postcode(s) [2] 25063 0
2050 - Camperdown
Recruitment postcode(s) [3] 25061 0
3065 - Fitzroy
Recruitment postcode(s) [4] 25057 0
3168 - Clayton
Recruitment postcode(s) [5] 25058 0
3050 - Parkville
Recruitment postcode(s) [6] 25056 0
3004 - Melbourne
Recruitment postcode(s) [7] 25064 0
2065 - St Leonards
Recruitment postcode(s) [8] 25068 0
5000 - Adelaide
Recruitment postcode(s) [9] 25066 0
2291 - Merewether
Recruitment postcode(s) [10] 25059 0
3084 - Heidelberg
Recruitment outside Australia
Country [1] 22011 0
New Zealand
State/province [1] 22011 0
Auckland and Canterbury

Funding & Sponsors
Funding source category [1] 296082 0
Other
Name [1] 296082 0
Baker Heart and Diabetes Institute
Country [1] 296082 0
Australia
Funding source category [2] 296083 0
Commercial sector/Industry
Name [2] 296083 0
Genkyotex S.A.
Country [2] 296083 0
France
Funding source category [3] 296080 0
Charities/Societies/Foundations
Name [3] 296080 0
Juvenile Diabetes Research Foundation (JDRF). Australian Type 1 Diabetes Clinical Research Network research grant
Country [3] 296080 0
Australia
Primary sponsor type
Other
Name
Baker Heart and Diabetes Institute
Address
75 Commercial Road, Melbourne VIC 3004.
Country
Australia
Secondary sponsor category [1] 294979 0
None
Name [1] 294979 0
None
Address [1] 294979 0
None
Country [1] 294979 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297341 0
South Metropolitan Health Service Human Research Ethics Committee
Ethics committee address [1] 297341 0
Ethics committee country [1] 297341 0
Australia
Date submitted for ethics approval [1] 297341 0
11/04/2017
Approval date [1] 297341 0
Ethics approval number [1] 297341 0
Ethics committee name [2] 297339 0
Alfred Hospital Ethics Committee
Ethics committee address [2] 297339 0
Ethics committee country [2] 297339 0
Australia
Date submitted for ethics approval [2] 297339 0
20/03/2017
Approval date [2] 297339 0
23/06/2017
Ethics approval number [2] 297339 0
154/17

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 73750 0
Prof Jonathan Shaw
Address 73750 0
Baker Heart and Diabetes Institute,
Level 4, 99 Commercial Road
Melbourne VIC 3004
Country 73750 0
Australia
Phone 73750 0
+61 3 8532 1800
Fax 73750 0
Email 73750 0
jonathan.shaw@baker.edu.au
Contact person for public queries
Name 73751 0
Jonathan Shaw
Address 73751 0
Baker Heart and Diabetes Institute,
Alfred Centre
Level 4, 99 Commercial Road
Melbourne VIC 3004
Country 73751 0
Australia
Phone 73751 0
+61 3 8532 1800
Fax 73751 0
Email 73751 0
jonathan.shaw@baker.edu.au
Contact person for scientific queries
Name 73752 0
Mark Cooper
Address 73752 0
Monash University
Alfred Centre
Level 5, 99 Commercial Road
Melbourne VIC 3004
Country 73752 0
Australia
Phone 73752 0
+61 3 9903 0006
Fax 73752 0
Email 73752 0
mark.cooper@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA 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.2020https://dx.doi.org/10.1016/j.cct.2019.105892
EmbaseEvaluating the efficacy and safety of GKT137831 in adults with type 1 diabetes and persistently elevated urinary albumin excretion: A statistical analysis plan.2020https://dx.doi.org/10.1186/s13063-020-04404-0
EmbaseNADPH Oxidase Inhibition: Preclinical and Clinical Studies in Diabetic Complications.2020https://dx.doi.org/10.1089/ars.2020.8047
EmbaseDiabetic Kidney Disease: From Pathogenesis to Novel Treatment Possibilities.2022https://dx.doi.org/10.1007/164_2021_576
Dimensions AIPre-clinical evidence of a dual NADPH oxidase 1/4 inhibitor (setanaxib) in liver, kidney and lung fibrosis2023https://doi.org/10.1111/jcmm.17649
EmbaseOxidative stress and the role of redox signalling in chronic kidney disease.2024https://dx.doi.org/10.1038/s41581-023-00775-0
N.B. These documents automatically identified may not have been verified by the study sponsor.