A Pilot, Phase II Study With a Prospective, Randomized, Cross-Over, Placebo-Controlled, Double-Blind Design to Assess the Short-Term Effects of Tolvaptan Plus Placebo vs Tolvaptan Plus Octreotide LAR Combination Therapy in ADPKD Patients With Normal Kidney Function or Hyperfiltration
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Glomerular Filtration Rate (GFR)
研究概览
简要总结
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a leading cause of End Stage Kidney Disease (ESKD) worldwide. Elevated levels of 3', 5' - cyclic AMP (cAMP) play a central role in the pathogenesis and progression of the disease. Vasopressin antagonists and somatostatin analogues, which indirectly reduce adenyl cyclase 6 activity, have been found to markedly reduce renal tubular cell proliferation and cyst growth in experimental models of ADPKD. In combination, the two treatments show a clear additive effect and may significantly reduce renal cystic and fibrotic volume as well as cAMP levels to wild type levels.
The vasopressin antagonist Tolvaptan and the somatostatin analogue Octreotide share a similar renoprotective effect also in human disease.
Both medications effectively slow total kidney and cystic volume (TKV and TCV, respectively) growth and glomerular filtration rate (GFR) decline in patients with ADPKD. The short-term effect of both medications appear to be larger when the GFR is normal or even higher than normal and kidney volumes are still relatively stable. On the basis of experimental data, it is conceivable that Tolvaptan and Octreotide LAR should have an additive effect also in human disease, during initial treatment as well as in the long-term. To address the working hypothesis of an additional short-term effect of Tolvaptan and Octreotide, we propose to run a pilot, explorative, randomized, placebo-controlled, clinical trial with a Cross-Over Design to compare the short-term effects of Tolvaptan monotherapy and Tolvaptan plus Octreotide LAR combination therapy on TKV as assessed by MRI, and on GFR as directly measured by the iohexol plasma clearance technique in ADPKD patients with normal (80 to 120 ml/min/1.73m2) kidney function or even kidney hyperfiltration (GFR ≥120 ml/min/1.73m2).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult (>18-yr-old) men and women, with a clinical and ultrasonographic diagnosis of ADPKD;
- •Serum creatinine < 1.0 mg/dl (for man) and < 1.2 mg/dl (for woman) and changes in serum creatinine (and creatinine clearance when available) <30% over the last six months;
- •Creatinine clearance > 80 ml/min/1.73m2 measured one to two weeks apart during the pre-screening period;
- •GFR ≥ 80 ml/min/1.73m2 (by iohexol plasma clearance technique) at screening and baseline evaluations;
- •TKV ranging between 1000 and 2000 ml at screening (by ultrasound imaging) and at baseline (by MRI) evaluations;
- •Female participants must be of non-childbearing potential or must agree to abstinence or use a highly effective form of contraception;
- •Written informed consent.
排除标准
- •Patients with concomitant systemic, renal parenchymal or urinary tract disease;
- •Overt proteinuria (urinary protein excretion rate >1 g/24 hours);
- •Abnormal urinalysis suggestive of concomitant, clinically significant glomerular disease, urinary tract lithiasis, infection or obstruction, biliary tract lithiasis or obstruction;
- •Hemorrhagic or complicated cysts which might acutely affect kidney function and volumes;
- •QT-related ECG abnormalities;
- •Cancer and major systemic diseases that could prevent completion of the planned follow-up or interfere with data collection or interpretation;
- •Hypersensitivity to the IMP active substance or to any of the excipients or to benzazepine or benzazepine derivatives;
- •Concomitant treatment with drugs that may affect glomerular hemodynamics during the three months before the beginning of the study (including ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists and non-steroideal anti-inflammatory medications);
- •Elevated liver enzymes and/or signs or symptoms of liver injury prior to initiation of treatment that meet the requirements for permanent discontinuation of tolvaptan
- •Patients with anuria, volume depletion and hypernatraemia
- •Patients who cannot perceive or respond to thirst
- •Ferro-magnetic prosthesis, aneurysm clips, severe claustrophobia or any other contraindication to MRI evaluation;
- •Psychiatric disorders and any condition that could prevent full comprehension of the purposes and risks of the study;
- •Pregnant or lactating;
- •Participation in another interventional clinical trial within the 4 weeks prior to screening.
研究组 & 干预措施
Tolvaptan plus Octreotide LAR / Tolvaptan plus Placebo
Patients will receive a first 4-week treatment period with Tolvaptan up to 120 mg/die, according to tolerability, and a single dose of Octreotide LAR (two 20 mg i.m. injections). Then, after a period of wash-out, each patient will cross over to the other treatment arm for a second 4-week treatment period with Tolvaptan plus a single dose of placebo (two i.m. injections of 0.9% NaCl solution)
干预措施: Tolvaptan (Drug)
Tolvaptan plus Octreotide LAR / Tolvaptan plus Placebo
Patients will receive a first 4-week treatment period with Tolvaptan up to 120 mg/die, according to tolerability, and a single dose of Octreotide LAR (two 20 mg i.m. injections). Then, after a period of wash-out, each patient will cross over to the other treatment arm for a second 4-week treatment period with Tolvaptan plus a single dose of placebo (two i.m. injections of 0.9% NaCl solution)
干预措施: Octreotide LAR (Drug)
Tolvaptan plus Octreotide LAR / Tolvaptan plus Placebo
Patients will receive a first 4-week treatment period with Tolvaptan up to 120 mg/die, according to tolerability, and a single dose of Octreotide LAR (two 20 mg i.m. injections). Then, after a period of wash-out, each patient will cross over to the other treatment arm for a second 4-week treatment period with Tolvaptan plus a single dose of placebo (two i.m. injections of 0.9% NaCl solution)
干预措施: Placebo (Other)
Tolvaptan plus placebo/Tolvaptan plus Octreotide LAR
Patients will receive a first 4-week treatment period with Tolvaptan up to 120 mg/die, according to tolerability, and a single dose of placebo (two i.m. injections of 0.9% NaCl solution). Then, after a period of wash-out, each patient will cross over to the other treatment arm for a second 4-week treatment period with Tolvaptan plus a single dose of Octreotide LAR (two 20 mg i.m. injections).
干预措施: Tolvaptan (Drug)
Tolvaptan plus placebo/Tolvaptan plus Octreotide LAR
Patients will receive a first 4-week treatment period with Tolvaptan up to 120 mg/die, according to tolerability, and a single dose of placebo (two i.m. injections of 0.9% NaCl solution). Then, after a period of wash-out, each patient will cross over to the other treatment arm for a second 4-week treatment period with Tolvaptan plus a single dose of Octreotide LAR (two 20 mg i.m. injections).
干预措施: Octreotide LAR (Drug)
Tolvaptan plus placebo/Tolvaptan plus Octreotide LAR
Patients will receive a first 4-week treatment period with Tolvaptan up to 120 mg/die, according to tolerability, and a single dose of placebo (two i.m. injections of 0.9% NaCl solution). Then, after a period of wash-out, each patient will cross over to the other treatment arm for a second 4-week treatment period with Tolvaptan plus a single dose of Octreotide LAR (two 20 mg i.m. injections).
干预措施: Placebo (Other)
结局指标
主要结局
Glomerular Filtration Rate (GFR)
时间窗: Changes from 4 weeks before randomization at baseline, 1,4,8,9,12 and 16 weeks after the randomization.
GFR will be assessed by the Iohexol Plasma Clearance Technique
次要结局
- Total Kidney Volume (TKV)(Changes from baseline at 4,8,12 and 16 weeks after the randomization.)