Type 2 Diabetes Mellitus With Diabetic Nephropathy
Conditions
Keywords
Type 2 diabetes, Proteinuria, Albuminuria
Brief summary
NADPH oxidase enzymes (NOX) have been implicated in the development of several diabetic complications including diabetic nephropathy. GKT137831 is the first in class NOX1/4 inhibitor. The primary objective of this study is to evaluate the efficacy of oral GKT137831 in patients with residual albuminuria despite maximal inhibition of the renin angiotensin aldosterone system.
Detailed description
A double-blind, placebo-controlled, randomized, multicenter, parallel group Phase 2 study assessing a 12-week period of treatment with oral GKT137831 administered in addition to standard of care for patients with type 2 diabetes.
Interventions
DRUGGKT137831
1 capsule of 100 mg twice a day for the first 6 weeks of treatment, and 2 capsules of 100 mg twice a day for next 6 weeks of treatment
DRUGPlacebo
1 capsule of Placebo, twice a day, oral treatment self-administered by the patient for the 12 weeks of treatment.
Sponsors
Calliditas Therapeutics AB
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Male or female aged 18 to 80 years * History of type 2 diabetes, defined as fasting plasma glucose ≥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. * Albuminuria defined as a UACR of 300 to 3500 mg/g. * An eGFR ≥30 mL/min/1.73 m2, as calculated by the CKD-EPI formula. * 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. Key
Exclusion criteria
* History of type 1 diabetes * Any other non-diabetic kidney disease(s) except for hypertensive nephropathy which is acceptable. * Diagnostic or interventional procedure requiring a contrast agent within 4 weeks of the first screening visit (Visit 1) or planned during the study. * History of renal transplant or planned renal transplant during the study. * 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) * HbA1c level \>11% (97 mmol/mol). * History of hypothyroidism requiring hormone replacement therapy. * History of active cardiovascular disease * A personal or family history of long QT syndrome. * Administration of any investigational product within 30 days or within 5 half-lives of the investigational agent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Albuminuria Absolute Value and Ratio to Baseline by Study Visit and Treatment Group | Visit 4 (week -2) to visit 11 (week 12) | UACR from baseline to Visits 9, 10, and 11 (i.e. weeks 8, 10 and 12 of the treatment period, respectively). Baseline for UACR is defined as the geometric mean of the geometric means of the UACR values measured on Day-14 (visit 4) and Day 1 (visit 5). End of treatment is defined as the geometric mean of the geometric means of the UACR values measured at week 8 (visit 9), week 10 (visit 10) and week 12 (visit 11). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Glucose Metabolism by Homeostatic Model Assessment (HOMA) | Visits 5 (week 0), 8 (week 6), and 11 (week 12) | Change in homeostasis model assessment-estimated β cell function (HOMA-B) and homeostasis model assessment-estimated insulin resistance (HOMA-IR) from baseline. HOMA-IR = fasting insulin (μIU/mL) x fasting glucose (mM/L)/22.5. A higher HOMA-IR value indicates greater insulin resistance. HOMA-B = 20 x fasting insulin (μIU/mL)/(fasting glucose \[mmol/mL\] - 3.5). Generally, a higher HOMA-B value indicates better beta-cell function, meaning the pancreas is producing insulin effectively. |
| Glucose Metabolism HbA1c | Visit 5 (week 0), 8 (week 6) and 11 (week 12) | Change in HbA1c from Baseline |
| 24 Hours Albumin Excretion | Visits 5 (week 0) and 11 (week 12) | Change in 24 hours Albumin excretion from baseline |
| 24 Hours Urine UACR | Visits 5 (week 0) and 11 (week 12) | Change in 24 hours Urine UACR from baseline |
| eGFR Change by Study Visit | Visits 5 (week 0), 6 (week 2), 7 (week 4), 8 (week 6), 9 (week 8), 10 (week 10), 11 (week 12), follow up (week 16) | Change in eGFR from baseline by study visit |
Other
| Measure | Time frame | Description |
|---|---|---|
| Erectile Dysfunction | Visits 5 (week 0), and 11 (week 12) | Changes at week 12 in IEFF questionnaire assessing erectile dysfunction in patients presenting with these diabetic complications at baseline (Baseline \<=25 in the erectile function domain)- Score from 1 to 30. Score 1 to 10: severe erectile dysfunction, Score 11-16: moderate erectile dysfunction, Score 17-25: light erectile dysfunction, Score 26-30: normal erectile function |
| Neuropathic Pain | Visits 5 (week 0), and 11 (week 12) | Changes in Visual Analog Scale (VAS) assessing neuropathic leg pain in patients presenting with these diabetic complications at baseline (subjects with a baseline VAS\>=20mm are included). A 100mm VAS scale was used with a range from 0-100mm where a higher score means worse pain. The presence of neuropathic pain is defined a VAS score of at least 20 mm. |
Countries
Australia, Canada, Czechia, Germany, Poland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GKT137831 GKT137831 100 mg capsules twice a day
GKT137831: 1 capsule of 100 mg twice a day for the first 6 weeks of treatment, and 2 capsules of 100 mg twice a day for next 6 weeks of treatment | 68 |
| Placebo Placebo capsule twice a day
Placebo: 1 capsule of Placebo, twice a day, oral treatment self-administered by the patient for the 12 weeks of treatment. | 68 |
| Total | 136 |
Baseline characteristics
| Characteristic | GKT137831 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 30 Participants | 25 Participants | 55 Participants |
| Age, Categorical Between 18 and 65 years | 38 Participants | 43 Participants | 81 Participants |
| Age, Continuous | 62.1 Years STANDARD_DEVIATION 8.64 | 62.2 Years STANDARD_DEVIATION 9.9 | 62.1 Years STANDARD_DEVIATION 9.24 |
| Region of Enrollment Australia | 5 participants | 11 participants | 16 participants |
| Region of Enrollment Canada | 12 participants | 9 participants | 21 participants |
| Region of Enrollment Czechia | 13 participants | 8 participants | 21 participants |
| Region of Enrollment Germany | 7 participants | 2 participants | 9 participants |
| Region of Enrollment Poland | 5 participants | 8 participants | 13 participants |
| Region of Enrollment United States | 26 participants | 30 participants | 56 participants |
| Sex: Female, Male Female | 16 Participants | 16 Participants | 32 Participants |
| Sex: Female, Male Male | 52 Participants | 52 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 68 | 0 / 68 |
| other Total, other adverse events | 33 / 68 | 42 / 68 |
| serious Total, serious adverse events | 3 / 68 | 5 / 68 |
Outcome results
Primary
Albuminuria Absolute Value and Ratio to Baseline by Study Visit and Treatment Group
UACR from baseline to Visits 9, 10, and 11 (i.e. weeks 8, 10 and 12 of the treatment period, respectively). Baseline for UACR is defined as the geometric mean of the geometric means of the UACR values measured on Day-14 (visit 4) and Day 1 (visit 5). End of treatment is defined as the geometric mean of the geometric means of the UACR values measured at week 8 (visit 9), week 10 (visit 10) and week 12 (visit 11).
Time frame: Visit 4 (week -2) to visit 11 (week 12)
Population: Number of subjects analyzed in the Intent to Treat population who have evaluable results
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| GKT137831 | Albuminuria Absolute Value and Ratio to Baseline by Study Visit and Treatment Group | Baseline Geom. Mean | 705.72 mg/g |
| GKT137831 | Albuminuria Absolute Value and Ratio to Baseline by Study Visit and Treatment Group | Adjusted End of treatment Geom. Mean | 758.22 mg/g |
| Placebo | Albuminuria Absolute Value and Ratio to Baseline by Study Visit and Treatment Group | Baseline Geom. Mean | 696.30 mg/g |
| Placebo | Albuminuria Absolute Value and Ratio to Baseline by Study Visit and Treatment Group | Adjusted End of treatment Geom. Mean | 705.29 mg/g |
Comparison: Primary efficacy endpoint was analyzed using ANCOVA comparing GKT137831 vs placebo after controlling for the baseline UACR level. The UACR were log-transformed prior to analysis. The model included treatment group and log-transformed baseline UACR value as predicted variables. The results were back-transformed exponentially to calculate geo. mean values and associated 90% CIs and 1-sided p-values. The null hypothesis was that the difference in the adjusted mean logarithm of UACR was equal to 0p-value: 1ANCOVA
Secondary
24 Hours Albumin Excretion
Change in 24 hours Albumin excretion from baseline
Time frame: Visits 5 (week 0) and 11 (week 12)
Population: Number of subjects analyzed in the intent to treat population who have evaluable results
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GKT137831 | 24 Hours Albumin Excretion | 389.82 mg/24hrs | Standard Deviation 1540.3 |
| Placebo | 24 Hours Albumin Excretion | -56.15 mg/24hrs | Standard Deviation 1569.23 |
Secondary
24 Hours Urine UACR
Change in 24 hours Urine UACR from baseline
Time frame: Visits 5 (week 0) and 11 (week 12)
Population: Number of subjects analyzed in the intent to treat population who have evaluable results
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GKT137831 | 24 Hours Urine UACR | 220.15 mg/g | Standard Deviation 592.995 |
| Placebo | 24 Hours Urine UACR | 169.98 mg/g | Standard Deviation 706.38 |
Secondary
eGFR Change by Study Visit
Change in eGFR from baseline by study visit
Time frame: Visits 5 (week 0), 6 (week 2), 7 (week 4), 8 (week 6), 9 (week 8), 10 (week 10), 11 (week 12), follow up (week 16)
Population: Number of subjects analyzed in the intent to treat Population who have evaluable results
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GKT137831 | eGFR Change by Study Visit | Change in week 6 (Visit 8) eGFR from baseline | -0.1 mL/min/1.73m^2 | Standard Deviation 8.13 |
| GKT137831 | eGFR Change by Study Visit | Change in week 10 (Visit 10) eGFR from baseline | -0.7 mL/min/1.73m^2 | Standard Deviation 8.21 |
| GKT137831 | eGFR Change by Study Visit | Change in week 4 (Visit 7) eGFR from baseline | -0.6 mL/min/1.73m^2 | Standard Deviation 8.25 |
| GKT137831 | eGFR Change by Study Visit | Change in week 12 (Visit 11) eGFR from baseline | -1.5 mL/min/1.73m^2 | Standard Deviation 8.28 |
| GKT137831 | eGFR Change by Study Visit | Change in week 8 (Visit 9) eGFR from baseline | -1.1 mL/min/1.73m^2 | Standard Deviation 8.7 |
| GKT137831 | eGFR Change by Study Visit | Change in week 16 (Follow up) eGFR from baseline | -1.3 mL/min/1.73m^2 | Standard Deviation 8.21 |
| GKT137831 | eGFR Change by Study Visit | Change in week 2 (Visit 6) eGFR from baseline | -0.5 mL/min/1.73m^2 | Standard Deviation 6.07 |
| Placebo | eGFR Change by Study Visit | Change in week 16 (Follow up) eGFR from baseline | -1.9 mL/min/1.73m^2 | Standard Deviation 10.45 |
| Placebo | eGFR Change by Study Visit | Change in week 2 (Visit 6) eGFR from baseline | -0.4 mL/min/1.73m^2 | Standard Deviation 7.27 |
| Placebo | eGFR Change by Study Visit | Change in week 4 (Visit 7) eGFR from baseline | -1.5 mL/min/1.73m^2 | Standard Deviation 6.55 |
| Placebo | eGFR Change by Study Visit | Change in week 6 (Visit 8) eGFR from baseline | -0.3 mL/min/1.73m^2 | Standard Deviation 6.8 |
| Placebo | eGFR Change by Study Visit | Change in week 8 (Visit 9) eGFR from baseline | -1.7 mL/min/1.73m^2 | Standard Deviation 7.31 |
| Placebo | eGFR Change by Study Visit | Change in week 10 (Visit 10) eGFR from baseline | -1.9 mL/min/1.73m^2 | Standard Deviation 7.89 |
| Placebo | eGFR Change by Study Visit | Change in week 12 (Visit 11) eGFR from baseline | -1.2 mL/min/1.73m^2 | Standard Deviation 8.08 |
Secondary
Glucose Metabolism by Homeostatic Model Assessment (HOMA)
Change in homeostasis model assessment-estimated β cell function (HOMA-B) and homeostasis model assessment-estimated insulin resistance (HOMA-IR) from baseline. HOMA-IR = fasting insulin (μIU/mL) x fasting glucose (mM/L)/22.5. A higher HOMA-IR value indicates greater insulin resistance. HOMA-B = 20 x fasting insulin (μIU/mL)/(fasting glucose \[mmol/mL\] - 3.5). Generally, a higher HOMA-B value indicates better beta-cell function, meaning the pancreas is producing insulin effectively.
Time frame: Visits 5 (week 0), 8 (week 6), and 11 (week 12)
Population: Number of subjects analyzed in the Intent to treat population who have evaluable results
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GKT137831 | Glucose Metabolism by Homeostatic Model Assessment (HOMA) | HOMA-IR Week 6 change from baseline | 0.916 score on a scale | Standard Deviation 2.84 |
| GKT137831 | Glucose Metabolism by Homeostatic Model Assessment (HOMA) | HOMA-B Week 6 change from baseline | 12.94 score on a scale | Standard Deviation 24.06 |
| GKT137831 | Glucose Metabolism by Homeostatic Model Assessment (HOMA) | HOMA-B Week 12 change from baseline | -12.41 score on a scale | Standard Deviation 38.72 |
| GKT137831 | Glucose Metabolism by Homeostatic Model Assessment (HOMA) | HOMA-IR Week 12 change from baseline | 0.344 score on a scale | Standard Deviation 2.32 |
| Placebo | Glucose Metabolism by Homeostatic Model Assessment (HOMA) | HOMA-B Week 12 change from baseline | 47.63 score on a scale | Standard Deviation 120.18 |
| Placebo | Glucose Metabolism by Homeostatic Model Assessment (HOMA) | HOMA-IR Week 6 change from baseline | 2.013 score on a scale | Standard Deviation 1.943 |
| Placebo | Glucose Metabolism by Homeostatic Model Assessment (HOMA) | HOMA-IR Week 12 change from baseline | -1.833 score on a scale | Standard Deviation 3.95 |
| Placebo | Glucose Metabolism by Homeostatic Model Assessment (HOMA) | HOMA-B Week 6 change from baseline | 50.10 score on a scale | Standard Deviation 75.81 |
Secondary
Glucose Metabolism HbA1c
Change in HbA1c from Baseline
Time frame: Visit 5 (week 0), 8 (week 6) and 11 (week 12)
Population: Number of subjects in the Intend to Treat Population who have evaluable results
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| GKT137831 | Glucose Metabolism HbA1c | Week 12 change from baseline | 0.12 percentage of glycated haemoglobin | Standard Deviation 0.659 |
| GKT137831 | Glucose Metabolism HbA1c | Week 6 change from baseline | 0.02 percentage of glycated haemoglobin | Standard Deviation 0.538 |
| Placebo | Glucose Metabolism HbA1c | Week 6 change from baseline | -0.03 percentage of glycated haemoglobin | Standard Deviation 0.618 |
| Placebo | Glucose Metabolism HbA1c | Week 12 change from baseline | 0.03 percentage of glycated haemoglobin | Standard Deviation 0.722 |
Other Pre-specified
Erectile Dysfunction
Changes at week 12 in IEFF questionnaire assessing erectile dysfunction in patients presenting with these diabetic complications at baseline (Baseline \<=25 in the erectile function domain)- Score from 1 to 30. Score 1 to 10: severe erectile dysfunction, Score 11-16: moderate erectile dysfunction, Score 17-25: light erectile dysfunction, Score 26-30: normal erectile function
Time frame: Visits 5 (week 0), and 11 (week 12)
Population: Number of subjects analyzed in the Intent to Treat population who have evaluable results
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GKT137831 | Erectile Dysfunction | 0.8 score on a scale | Standard Deviation 5.86 |
| Placebo | Erectile Dysfunction | -0.5 score on a scale | Standard Deviation 5.06 |
Other Pre-specified
Neuropathic Pain
Changes in Visual Analog Scale (VAS) assessing neuropathic leg pain in patients presenting with these diabetic complications at baseline (subjects with a baseline VAS\>=20mm are included). A 100mm VAS scale was used with a range from 0-100mm where a higher score means worse pain. The presence of neuropathic pain is defined a VAS score of at least 20 mm.
Time frame: Visits 5 (week 0), and 11 (week 12)
Population: Number of subjects analyzed in the Intent to treat population who have evaluable results
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| GKT137831 | Neuropathic Pain | -15.3 score on a scale | Standard Deviation 21.79 |
| Placebo | Neuropathic Pain | -10.5 score on a scale | Standard Deviation 22.18 |