A Study to Assess the Renoprotective Effects of the SGLT2 Inhibitor Dapagliflozin in Non-Diabetic Patients With Proteinuria: a Randomized Double Blind 6-Weeks Cross-Over Trial
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 53
- 试验地点
- 7
- 主要终点
- Change in 24-hr Proteinuria With Dapagliflozin for Six Weeks Relative to Placebo in Patients With Non-diabetic Kidney Disease and Proteinuria 500 mg/Day on Stable Angiotensin-converting Enzyme Inhibitor or Angiotensin II Receptor Blocker Treatment.
研究概览
简要总结
This study tests the hypothesis that dapagliflozin lowers proteinuria in patients with non-diabetic chronic kidney disease.
详细描述
Despite optimal treatment with renin-angiotensin-aldosterone-system (RAAS) inhibitors, many patients with non-diabetic kidney disease show progressive kidney function loss, which is associated with high residual proteinuria. Novel treatment strategies are therefore required to further decrease proteinuria and to slow kidney function decline.
Dapagliflozin is a sodium-glucose transport (SGLT2) inhibitor and inhibits the reabsorption of glucose and sodium in the proximal tubule. The increased natriuresis following dapagliflozin administration normalizes tubuloglomerular feedback resulting in a reduction in intra-glomerular hypertension, which is in turn manifested by acute reversible reductions in glomerular filtration rate and albuminuria. Since many etiologies of non-diabetic nephropathy are characterized by intraglomerular hypertension, we hypothesize that dapagliflozin acutely decreases GFR and proteinuria in patients without diabetes at risk of progressive kidney function loss via a glucose independent hemodynamic mechanism.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Prevention
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 and ≤75 years
- •Urinary protein excretion > 500 mg/g and ≤ 3500 mg/g in a 24-hr urine collection eGFR ≥ 25 mL/min/1.73m2
- •On a stable dose of an ACEi or ARB for at least 4 weeks prior to randomization
- •Willing to sign informed consent
- •Women of Child-Bearing Potential (WOCBP):
- •WOCBP must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of study drug in such a manner that the risk of pregnancy is minimized.
- •WOCBP must have a negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or equivalent units of HCG) within 0 to 72 hours before the first dose of study drug.
- •Women must not be breast-feeding.
- •WOCBP comprises women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal.
排除标准
- •Diagnosis of type 1 or type 2 diabetes mellitus
- •Urinary protein excretion > 3500 mg/day
- •Peripheral Vascular Disease
- •Autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis
- •Indication for immunosuppressants as per the treating physician's judgment.
- •Receiving cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment.
- •Active malignancy aside from treated squamous cell or basal cell carcinoma of the skin.
- •Use of co-interventional treatments (outlined in section 4.2 of the protocol) within 6 weeks of screening will not be allowed.
- •Any medication, surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of medications including, but not limited to any of the following:
- •History of active inflammatory bowel disease within the last six months;
- •Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection;
- •Gastro-intestinal ulcers and/or gastrointestinal or rectal bleeding within last six months;
- •Pancreatic injury or pancreatitis within the last six months;
- •Evidence of hepatic disease as determined by any one of the following: ALT or AST values exceeding 3x ULN at the screening visit, a history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt;
- •Evidence of urinary obstruction of difficulty in voiding at screening
- •History of severe hypersensitivity or contraindications to dapagliflozin
- •Subject who, in the assessment of the investigator, may be at risk for dehydration or volume depletion that may affect the interpretation of efficacy or safety data
- •Participation in any clinical investigation within 3 months prior to initial dosing.
- •Donation or loss of 400 ml or more of blood within 8 weeks prior to initial dosing.
- •History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during the screening.
- •History of noncompliance to medical regimens or unwillingness to comply with the study protocol.
- •Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study.
- •Pregnancy or breastfeeding
- •WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and up to 4 weeks after the last dose of study drug.
研究组 & 干预措施
Dapagliflozin 10mg Tablet, then Placebo
Participants first received Dapagliflozin 10mg tablet for 6 weeks. After a washout period of 6 weeks, they then received Placebo tablet for 6 weeks (matching Dapagliflozin 10mg).
Dapagliflozin 10 mg: Green, plain, diamond shaped, film coated tablet (orally) Placebo: Green, plain, diamond shaped, film coated tablet. Does not contain active ingredient
干预措施: Dapagliflozin 10mg (Drug)
Placebo, then Dapagliflozin
Participants first received Placebo tablet for 6 weeks. After a washout period of 6 weeks, they then received Dapagliflozin 10mg tablet for 6 weeks (matching Dapagliflozin 10mg).
Placebo: Green, plain, diamond shaped, film coated tablet. Does not contain active ingrediënt Dapagliflozin 10 mg: Green, plain, diamond shaped, film coated tablet (orally)
干预措施: Dapagliflozin 10mg (Drug)
结局指标
主要结局
Change in 24-hr Proteinuria With Dapagliflozin for Six Weeks Relative to Placebo in Patients With Non-diabetic Kidney Disease and Proteinuria 500 mg/Day on Stable Angiotensin-converting Enzyme Inhibitor or Angiotensin II Receptor Blocker Treatment.
时间窗: 6 weeks
bioequivalence
次要结局
- Effect of Dapagliflozin 10 mg/d Compared to Placebo on Adenosine/Creatinine Ratio(Baseline, Week 6)
- Effect of Dapagliflozin 10 mg/d Compared to Placebo on NTproBNP(Baseline (week 0, week 12), Week 6 + 18 (pooled))
- Effect of Dapagliflozin 10 mg/d Compared to Placebo on Glomerular Filtration Rate (GFR) Using Iohexol Clearance(6 weeks)
- Effect of Dapagliflozin 10 mg/d Compared to Placebo on Body Weight(week 0, 3, 6, 12, 15, 18, 24)
- Safety of Dapagliflozin vs. Placebo - the Number of Participatns With Hypoglycemic Events and/or Serious Adverse Events(week 0-26)
- Effect of Dapagliflozin 10 mg/d Compared to Placebo on Prostaglandin E2/Creatinine Ratio(Baseline, Week 6)
- Effect of Dapagliflozin 10 mg/d Compared to Placebo on 6-keto-Prostaglandin F1 Alpha/Creatinine Ratio(Baseline, Week 6)
- Effect of Dapagliflozin 10 mg/d Compared to Placebo on Thromboxane B2/Creatinine Ratio(Baseline, Week 6)
- Effect of Dapagliflozin 10 mg/d Compared to Placebo on PGEM/Creatinine Ratio(Baseline, Week 6)
- Effect of Dapagliflozin 10 mg/d Compared to Placebo on Systolic/Diastolic Blood Pressure(week 0, 3, 6, 12, 15, 18, 24)
研究者
Hiddo Lambers Heerspink
Clinical Pharmacologist
University Medical Center Groningen