E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with type 2 diabetes and albuminuria. |
|
E.1.1.1 | Medical condition in easily understood language |
Patients who have been told they have Type 2 diabetes that is they cannot metabolise sugar in the normal manner or the presence of a type of protein, albumin in their urine |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061835 |
E.1.2 | Term | Diabetic nephropathy |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10001580 |
E.1.2 | Term | Albuminuria |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of oral GKT137831 in comparison with placebo, in patients with type 2 diabetes and albuminuria. |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the safety of oral GKT137831 in comparison with placebo, in patients with type 2 diabetes and albuminuria.
To characterize the Pharmacodynamics of GKT137831 in this patient population, along with GKT137831 plasma concentrations, and any Pharmacokinetic/Pharmacodynamic relationship. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female aged 18 to 80 years, inclusive.
2. Willing and able to give written informed consent and to comply with
the requirements of the study.
3. History of type 2 diabetes, defined as fasting plasma glucose > or
equal to 7.0 mmol/L (126 mg/dL) or a glycated
hemoglobin (HbA1c) >6.5% (48 mmol/mol) on at least 2 occasions prior
to screening. If the diagnosis of type 2 diabetes has been made before
30 years of age, an optional fasting C-peptide level will be obtained
during the second screening visit (Visit 2) and must be > or equal to 0.1
ng/mL to confirm type 2 diabetes.
4. Albuminuria defined as a urinary albumin to creatinine ratio (UACR)
of:
- (a) 300 to 3500 mg/g (33.9 to 395.5 mg/mmol) during the screening
period to be eligible to enter the run-in period, determined as described
in the Methodology section.
- (b) 200 to 3500 mg/g ( 22.6 to 395.5 mg/mmol) by Week-2 (Visit 4) of
the run-in period to be eligible to enter the double-blind treatment
period, determined as described in the Methodology section.
5. An eGFR > or equal to 30 mL/min/1.73 m2, as calculated by the
CKD-EPI formula.
6. Must be taking an ACEI or an ARB for at least 6 weeks prior to the first
screening visit (Visit 1) and during the screening period. The dose must
have been stable for at least 4 weeks prior to the first screening visit
(Visit 1). Combination therapy associating an ACEI and an ARB is not
permitted.
7. 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 and the run-in
period, while taking investigational product and for at least 90 days
since the last dose of investigational product is ingested. Women of
childbearing potential are female patients 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 patients must also not donate sperm from Day
1/Baseline (Visit 5) until 90 days after the last dose of investigational
product. In the German territory, women of childbearing potential are
not eligible to enter the study. |
|
E.4 | Principal exclusion criteria |
1. A positive pregnancy test or breast-feeding for female patients.
2. History of type 1 diabetes.
3. Any other non-diabetic kidney disease(s) except for hypertensive
nephropathy which is acceptable.
4. Diagnostic or interventional procedure requiring a contrast agent
within 4 weeks of the first screening visit (Visit 1) or planned during the
study.
5. History of renal transplant or planned renal transplant during the
study.
6. A history of acute renal dialysis or acute kidney injury (defined
according to the Kidney Disease: Improving Global Outcomes [KDIGO]
definition) within 12 weeks of the first screening visit (Visit 1)
7. A body mass index (BMI) <18.5 kg/m2.
8. Elevated liver enzymes (alkaline phosphatase or alanine
aminotransferase [ALT]) >3 x the upper limit of normal (ULN), or
bilirubin >1.5 x the ULN) during the screening period (to enter the run-in
period) and during the run-in period (to enter the double-blind
treatment period).
9. HA1c level >11% (97 mmol/mol).
10. Inadequately controlled arterial blood pressure, defined as:
a) SBP >180 mmHg and <110 mmHg at the screening visits to be eligible
to enter the run-in period, determined as described in Section 9.1.1.
b) SBP >160 mmHg and <110 mmHg at Visit 5 to enter the double-blind
treatment period, determined as described in Section 9.1.1.
11. History of hypothyroidism requiring hormone replacement therapy
unless the dose of thyroid hormone(s) has been stable at least 4 weeks
prior to the Visit 1 and the TSH value is not greater then upper limit of
the normal range at Visit 1.
12. History of active cardiovascular disease defined as the occurrence of
the following events or conditions within the 12 weeks preceding the
first screening visit (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.
13. A personal or family history of long QT syndrome.
14. Evidence of any of the following cardiac conduction abnormalities
during the screening period (to enter the run-in period) and during the
run-in period (to enter the double-blind treatment period):
- A QTc Fredericia interval >450 milliseconds for males and >470
milliseconds for females.
- A second or third degree atrioventricular block not successfully treated
with a pacemaker.
15. History of cancer in the preceding 5 years, except adequately treated
non-melanoma skin cancer, carcinoma in situ of the cervix, in situ
prostate cancer, in situ breast ductal carcinoma, or superficial bladder
cancer (stage 0).
16. Current history of drug or alcohol abuse, as assessed by the
Investigator.
17. The occurrence of any acute infection requiring systemic antibiotic
therapy within the 2 weeks prior to the first day of the run-in period,
Week -4 (Visit 3), or infection with hepatitis B, hepatitis C, or human
immunodeficiency virus (HIV) infection.
18. A history of bone marrow disorder including aplastic anemia, or
marked anemia defined as hemoglobin <10.0 g/dL (or 6.2 mmol/L)
during screening.
19. 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 run-in period, Week -4 (Visit 3).
20. Any condition which, in the opinion of the Investigator, constitute a
risk or contraindication for the participation of the patient in the study,
or that could interfere with the study objectives, conduct, or evaluation.
21. Use of the following medications within 4 weeks of the first
screening visit: direct renin inhibitors, mineralocorticoid receptor
antagonists, EPO, endothelin receptor antagonists and or a history of
systemic immunosuppression for more than 2 weeks, cumulatively,
within the 12 weeks prior to the first screening visit or anticipated need
for immunosuppression during the study.
22. Major protocol deviation during the run-in period, subject to an
evaluation by the Investigator. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary variable for the evaluation of therapeutic efficacy will be albuminuria. Albuminuria will be characterized as the geometric mean of 2 consecutive early morning urine albumin/creatinine ratios (UACRs) collected twice during the baseline period (Visits 4 and 5), and then during the double-blind treatment period (Visits 6, 7, 8, 9, 10, 11, and 12). The primary efficacy endpoint will be defined as the change from baseline to the log-transformed geometric mean of the UACR measurements during Visits 9, 10, and 11. Baseline UACR will be defined as the geometric mean of UACR measurements at Visit 4 and Visit 5.
If there is at least 1 UACR value available at Visits 9, 10 or 11 the primary endpoint will be computed using all the available values. If all UACR measurements are missing at Visits 9, 10 and 11 the last non-missing value from Visit 8 will be used. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary efficacy endpoint will be defined as the change from baseline to the log-transformed geometric mean of the urine albumin/creatinine ratios (UACR) measurements during Visits 9, 10, and 11 (study weeks 8, 10 and 12). |
|
E.5.2 | Secondary end point(s) |
Efficacy end points:
24-hour albumin excretion will be determined at Baseline (Visit 5) and
end of treatment (Visit 11).
eGFR will be analyzed on an exploratory basis to verify that changes in UACR are not due to changes in eGFR.
Glucose metabolism:
- In patients not receiving insulin or secretagogues, homeostasis model assessment-estimated insulin resistance (HOMA-IR) and HOMA-estimated B-cell function (HOMA-B) determined at Day 1/Baseline (Visit 5) and Weeks 6 and 12 (Visits 8 and 11).
- Glycemic control, as determined from HbA1c at second screening visit (Visit 2), Day 1/Baseline (Visit 5) and at Weeks 6 and 12 (Visits 8 and 11).
- Diabetic peripheral neuropathy assessed using a 100 mm visual analogue scale (VAS) at Day 1/Baseline (Visit 5) and Week 12 (Visit 11).
- Erectile dysfunction assessed using the International Index of Erectile Function (IIEF) questionnaire at Day 1/Baseline (Visit 5) and Week 12 (Visit 11).
Safety End points:
Adverse events (AEs). Monitoring for AEs at all visits.
Laboratory tests:
- Clinical safety tests at the second screening visit (Visit 2), Weeks -2 to 16 (Visits 4 to 12):
- Hematology: hematocrit, hemoglobin, reticulocyte count, red blood cell (RBC) count, white blood cell (WBC) count, differential WBC count, and platelet count.
- A plasma sample for the determination of erythropoietin will be taken from all patients at Day 1/Baseline (Visit 5), Week 6 (Visit 8) and Week 12 (Visit 11). In case a retest is necessary due to a reduction in reticulocyte count the retest sample will be used to measure the standard hematology parameters and eythropoietin.
- Biochemistry: fasting glucose, creatinine, urea, sodium, potassium, chloride, aspartate aminotransferase (AST), ALT, total bilirubin, alkaline phosphatase, and gamma-glutamyl transferase (GGT), and total bile acids.
- Urinalysis: quantitative test for pH and protein; qualitative tests for glucose, ketones, bilirubin, blood; microscopic examination of the sediment. Additional dipstick test at the first screening visit (Visit 1).
- Viral serology performed at Visit 2: HIV antibodies (1 and 2), hepatitis B surface antigen and hepatitis C virus antibodies.
- Tests for thyroid stimulating hormone (TSH) performed at Day 1/Baseline (Visit 5) and Weeks 6, 12 and 16 (Visits 8, 11 and 12): free thyroxine (FT4) and thyroglobulin will be tested if TSH is abnormal.
- Blood lipid tests performed at Day 1/Baseline (Visit 5) and Weeks 6 and 12 (Visits 8 and 11): total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides.
Vital signs: oral temperature, at the first screening visit (Visit 1) and Week 16 follow-up (Visit 12); pulse rate, SBP and DBP at all visits.
- 12-lead electrocardiogram (ECG) at the second screening visit (Visit 2), Day 1/Baseline (Visit 5) and Weeks 2, 4, 6, 8, 10, 12 and 16 (Visits 6, 7, 8, 9, 10, 11, and 12, respectively).
- Complete physical examination at the first screening visit (Visit 1) and Week 16 follow-up (Visit 12); symptom-directed physical examination (associated with occurrence of AEs) at all other visits.
Pharmacodynamics:
The PD markers will be assessed in serum and/or plasma, or urine (samples taken at Day 1/Baseline, Weeks 6, 12 and Follow-up [Visits 5, 8 and 11 and 12]) include:
- Metabolic and inflammatory biomarkers: adiponectin, high sensitivity C-reactive protein (hs-CRP), leptin, monocyte chemotactic protein-1 (MCP-1), serum plasminogen activator inhibitor-1 (PAI-1), resistin, soluble tumor necrosis factor type 1 receptor (sTNFR1), and vascular cell adhesion molecule-1 (VCAM-1).
- Renal oxidative stress: urinary MCP-1,transforming growth factor- beta1 (TGF-beta1) and aldosterone.
- Optionally, additional biomarkers of interest will be measured. The identity of these exploratory markers will be defined in response to findings described in the literature or obtained in this study. These markers will not have diagnostic or prognostic value and will not have an established normal range according to the World Health Organization (WHO).
Pharmacokinetics:
Venous blood samples will be collected at Weeks 2, 6, 8 and 12 (Visits 6, 8, 9 and 11) in order to determine plasma drug
concentrations and investigation of any PK/PD relationship with PD and/or efficacy endpoints, and optionally for the relationships between PK parameters and pharmacogenomics data.
Pharmacogenetics:
Genetic and pharmacogenetic research may be conducted on the DNA samples collected at Day 1/Baseline (Visit 5) from patients who sign an optional, additional informed consent. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy end points:
24-hour albumin excretion - Day 1/ Baseline, end of treatment
eGFR - Day 1/Baseline, Week 2, 4, 6, 8, 10, 12.
Glucose metabolism and Glycemic control - Day 1/Baseline, Weeks 6 and
12.
Diabetic peripheral neuropathy and Erectile dysfunction - Day
1/Baseline, and Week 12.
Safety End points:
Adverse events (AEs)- assessed at all visits.
Clinical safety tests at the second screening visit (Visit 2), and Weeks -2
to 16.
Pharmacodynamic markers - samples taken at Day 1/Baseline, Weeks 6,
12 and Follow-up.
Pharmacokinetic markers - samples taken at Weeks 2, 6, 8 and 12. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 34 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |