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Program of ipragliflozin for endothelial dysfunction in chronic kidney disease and type 2 diabetes: a multicenter, randomized-controlled, open-label trial (PROCEED)

Program of ipragliflozin for endothelial dysfunction in chronic kidney disease and type 2 diabetes: a multicenter, randomized-controlled, open-label trial (PROCEED)

111

The predefined full analysis set (FAS) is the subject of the description. Each item is described in the following order: ipragliflozin group, control group, and the data are indicated as number (frequency in each group), mean +- SD, or median [IQR]. Number of persons in each treatment group: 53 (100%), 55 (100%) Age: 68.0 +- 11.6 years, 69.9 +- 10.5 years Gender (female): 20 (37.7%), 19 (34.5%) BMI: 26.14+-4.51 kg/m2, 24.74+-3.36 kg/m2 Duration of diabetes: 10.88 [4.71, 18.31] years, 13.00 [6.00, 18.00] years HbA1c: 7.3+-0.8%, 7.2+-0.8 eGFR: 58.3+-18.2 mL/min/1.73m2, 59.6+-17.2 mL/min/1.73m2 Urinary albumin-creatinine ratio: 49.50 [17.45, 118.25] mg/g cre, 55.35 [21.25, 116.25] mg/g cre RHI: 1.585+-0.265 (1.580 [1.390, 1.800]), 1.555+-0.251 (1.530 [1.420, 1.755]) LnRHI: 0.447+-0.170 (0.457 [0.329, 0.588]), 0.428+-0.167 (0.425 [0.351, 0.562]) Active smoking_yes: 14 (26.4%), 12 (21.8%) History of hypertension_yes: 43 (81.1%), 46 (83.6%) History of dyslipidemia_yes: 43 (81.1%), 44 (80.0%) History of heart failure_yes: 4 (7.5%), 3 (5.5%) Use of metformin_yes: 24 (45.3%), 31 (56.4%) Use of DPP-4 inhibitor_yes: 30 (56.6%), 38 (69.1%) Use of insulin_yes: 1 (1.9%), 1 (1.8%) Use of GLP-1 receptor agonist_yes: 1 (1.9%), 1 (1.8%) Use of ACE inhibitors_yes: 1 (1.9%), 3 (5.5%) Use of ARB_yes: 34 (64.2%), 37 (67.3%) Use of Ca channel blocker_yes: 25 (47.2%), 25 (45.5%) Use of beta-blockers_yes: 8 (15.1%), 4 (7.3%) Use of statin_yes: 25 (47.2%), 31 (56.4%)

Number of patients who signed informed consent: 179 patients Number of patients enrolled: 111 patients Number of patients who received protocol treatment: 111 patients (Ipragliflozin group: 56 patients / Control group: 55 patients) Discontinued: 6 patients (Ipragliflozin group: 5 patients / Control group: 1 patient) Number of patients who completed protocol treatment: 105 patients (Ipragliflozin group: 51 patients / Control group: 54 patients)

Events reported on periodic report: 2 cases - Drug eruption (Ipragliflozin group) - Weakness in the legs (Ipragliflozin group) Serious adverse event: 7 cases - Pneumonia, Lung cancer (Control group) - Exacerbation of cervical spondylosis (Control group) - Head injury (Control group) - Eosinophilic granulomatosis with polyangiitis (Control group) - Surgery for inguinal hernia (Ipragliflozin group) - Acute myocardial infarction (Control group) - Proximal end of the left humerus fracture (Closed fracture) (Ipragliflozin group)

Primary endpoint Change in natural log-transformed RHI (LnRHI) from baseline to 24 weeks after protocol treatment initiation or discontinuation: between-group difference 0.033 (95% CI -0.081 to 0.148), P=0.565 Secondary endpoints (1) Percent change in LnRHI from baseline to 24 weeks after protocol initiation or discontinuation: 22.9% (95%CI -29.1% to 75.0%), P=0.384 2) Prevalence of patients whose LnRHI increased by 15% or more from baseline at 24 weeks after protocol initiation or discontinuation: 28 patients (53.8% in the ipragliflozin group) vs. 25 patients (47.2% in the control group), P=0.416 3) Prevalence of patients with RHI in the normal range (>=2.10) at 24 weeks after initiation or discontinuation of protocol treatment: 9 patients (17.3% in the ipragliflozin group) vs. 15 patients (27.8% in the control group), P=0.185 (4) Prevalence of patients with LnRHI increased by 15% or more from baseline or with RHI in the normal range (2.10 or more) at 24 weeks after initiation or discontinuation of protocol treatment: 28 patients (53.8% in the ipragliflozin group) vs. 26 patients (48.1% in the control group), P=0.433 (5) Prevalence of patients whose LnRHI decreased by 15% or more from baseline at 24 weeks after initiation or discontinuation of protocol treatment: 10 (19.2% in the ipragliflozin group) vs. 16 (30.2% in the control group), P=0.172

In patients with type 2 diabetes and chronic kidney disease enrolled in the study, 24 weeks of ipragliflozin treatment, compared to standard therapy, had no statistically significant effect on vascular endothelial function as assessed by the RHI.

June. 30, 2023

May. 01, 2023

https://www.sciencedirect.com/science/article/pii/S1262363623000290

No

No

https://jrct.niph.go.jp/latest-detail/jRCTs071190054

Node Koichi

Saga University Hospital

1-1, 5-chome, Nabeshima, Saga-shi

node@cc.saga-u.ac.jp

Tanaka Atsushi

Saga University Hospital

1-1, 5-chome, Nabeshima, Saga-shi

+81-952-34-2364

tanakaa2@cc.saga-u.ac.jp

Complete

Mar. 25, 2020

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1. Adults with >= 30 years
2. T2D with 6.0 % <= HbA1c < 9.0 %
3. CKD with (i) [30 <= estimated glomerular filtration ratio (eGFR) < 60] or (ii) [albuminuria >= 30 mg/g CR]
4. RHI < 2.10 at pre-testing RH-PAT within 3 months prior to randomization (RHI >= 2.10 is recognized as normal endothelial function)
5. The patient provided written informed consent to participate in the study

1. Type 1 diabetes
2. History of clinically apparent atherosclerotic cardiovascular diseases, such as coronary artery disease, stroke, peripheral artery disease, symptomatic carotid artery stenosis
3. Chronic atrial fibrillation
4. History of severe ketosis, diabetic coma, or precoma attack <= 6 months prior to informed consent
5. Severe renal dysfunction (eGFR < 30 mL/min/1.73m2 or undergoing dialysis)
6. Patients received SGLT2 inhibitors within 3 month before informed consent
7. Patients who have changed the type or dose of antidiabetic drugs within 3 months before informed consent
8. Hypersensitivity to ipragliflozin or other SGLT2 inhibitors
9. Symptomatic hypotension, or systolic blood pressure < 90 mm Hg
10. Patients with severe infection or trauma at screening
11. Patients in perioperative period around screening
12. Polysystic kidney disease, lupus nephritis, or ANCA-related vasculitis
13. Pregnant or suspected pregnancy
14. Considered inappropriate for the study by investigators due to other reasons, such as malignancy and suspected poor compliant with clinic visits or prescribed medication

Both

Patients with Type 2 diabetes and established CKD

1) Ipuragliflozin group:
Participants who are assigned to the ipragliflozin group orally receive ipragliflozin 50 mg once daily in addition to their background medical therapy for diabetes. If the personalized goal is not achieved, the dose of ipragliflozin can be increased by the investigators to 100 mg once daily.
Control group: Participants who are assigned to the control group continue to receive their background medical therapy for diabetes.
2) In addition to the blood sampling performed in an usual medical care, an additional blood sample of 6 mL/visit for plasma biomarker measurements are further collected at baseline and at 24 weeks (or at discontinuation) (Total 12 mL).

The change amount in RHI automatically calculated by RH-PAT device from baseline to 24 weeks or at discontinuation of the treatment

1. The rate of change in RHI automatically calculated by RH-PAT device from baseline to 24 weeks or at discontinuation of the treatment
2. Prevalence of patients whose RHI substantially increase (LnRHI >15%) from baseline to 24 weeks or at discontinuation of the treatment
3. Prevalence of patients whose RHI recover within normal range (>= 2.10) at 24 weeks
4. Prevalence of patients whose RHI recover within normal range (>= 2.10) or substantially increase (LnRHI >15%) from baseline to 24 weeks or at discontinuation of the treatment
5. Prevalence of patients whose RHI substantially decrease (LnRHI >15%) from baseline to 24 weeks or at discontinuation of the treatment

+81-952-34-3357

Mar. 11, 2020

none