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Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial.

ABSTRACT: Evidence increasingly points to the importance of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal disease (ESRD). Beraprost sodium (BPS) is an orally active prostacyclin (PGI2) analogue demonstrating prevention of the progression of chronic kidney disease (CKD) in various animal models by maintaining renal blood flow and attenuating renal ischemic condition.This multicenter, randomized, double-blind, placebo-controlled, phase II trial was designed to determine the recommended dose of the sustained-release form of BPS (TRK-100STP 120 ?g/day or 240 ?g/day) in Japanese patients with CKD. TRK-100STP was administered to a total of 112 patients. The primary efficacy endpoint was the difference in the slope of the regression line of reciprocal of serum creatinine (1/SCr) over time, obtained by the least-squares method.Regarding the primary endpoint, statistical superiority of TRK-100STP 240 ?g over placebo was not confirmed and so a recommended dose was not determined. Compared to placebo, however, the slope of regression line of 1/SCr, elevation of SCr and serum cystatin C during the treatment period revealed greater improvement at 120 ?g, at both doses, and at 240 ?g, respectively. In terms of safety, both TRK-100STP treatment groups were well tolerated.Although the study failed to meet the primary endpoint, results indicate that TRK-100STP may potentially prevent the decline in renal function of CKD patients independent of blood pressure or urinary protein levels.NCT02480751. June 21, 2015.

SUBMITTER: Koyama A

PROVIDER: S-EPMC4608181 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial.

Koyama Akio A Fujita Toshiro T Gejyo Fumitake F Origasa Hideki H Isono Masanao M Kurumatani Hajimu H Okada Kiyonobu K Kanoh Hiroyuki H Kiriyama Takashi T Yamada Shunsuke S

BMC nephrology 20151016

<h4>Background</h4>Evidence increasingly points to the importance of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal disease (ESRD). Beraprost sodium (BPS) is an orally active prostacyclin (PGI2) analogue demonstrating prevention of the progression of chronic kidney disease (CKD) in various animal models by maintaining renal blood flow and attenuating renal ischemic condition.<h4>Methods</h4>This multicenter, randomized, double-blind, placebo-controlled, ph ...[more]

PMID: 26475266

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Project description:Three small trials suggest that intravenous immunoglobulin can affect biomarkers and symptoms of mild-to-moderate Alzheimer's disease. We tested the safety, effective dose, and infusion interval of intravenous immunoglobulin in such patients.We did a multicentre, placebo-controlled phase 2 trial at seven sites in the USA and five in Germany. Participants with probable Alzheimer's disease aged 50-85 years were randomly assigned (by a computer-generated randomisation sequence, with block sizes of eight) to infusions every 4 weeks (0·2, 0·5, or 0·8 g intravenous immunoglobulin per kg bodyweight, or placebo) or infusions every 2 weeks (0·1, 0·25, or 0·4 g/kg, or placebo). Patients, caregivers, investigators assessing outcomes, and staff at imaging facilities and the clinical research organisation were masked to treatment allocation, but dispensing pharmacists, the statistician, and the person responsible for final PET analyses were not. Treatment was masked with opaque pouches and infusion lines. The primary endpoint was median area under the curve (AUC) of plasma amyloid ? (A?)(1-40) between the last infusion and the final visit (2 weeks or 4 weeks depending on infusion interval) in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT00812565) and controlled-trials.com (ISRCTN64846759).89 patients were assessed for eligibility, of whom 58 were enrolled and 55 included in the primary analysis. Median AUC of plasma A?(1-40) was not significantly different for intravenous immunoglobulin compared with placebo for five of the six intervention groups (-18·0 [range -1347·0 to 1068·5] for 0·2 g/kg, -364·3 [-5834·5 to 1953·5] for 0·5 g/kg, and -351·8 [-1084·0 to 936·5] for 0·8 g/kg every 4 weeks vs -116·3 [-1379·0 to 5266·0] for placebo; and -13·8 [-1729·0 to 307·0] for 0·1 g/kg, and -32·5 [-1102·5 to 451·5] for 0·25 g/kg every 2 weeks vs 159·5 [51·5 to 303·0] for placebo; p>0·05 for all). The difference in median AUC of plasma A?(1-40) between the 0·4 g/kg every 2 weeks group (47·0 [range -341·0 to 72·5]) and the placebo group was significant (p=0·0216). 25 of 42 (60%) patients in the intervention group versus nine of 14 (64%) receiving placebo had an adverse event. Four of 42 (10%) patients in the intravenous immunoglobulin group versus four of 14 (29%) receiving placebo had a serious adverse event, including one stroke in the intervention group.Intravenous immunoglobulin may have an acceptable safety profile. Our results did not accord with those from previous studies. Longer trials with greater power are needed to assess the cognitive and functional effects of intravenous immunoglobulin in patients with Alzheimer's disease.

Project description:BackgroundInnovative approaches are needed to complement existing tools for malaria elimination. Ivermectin is a broad spectrum antiparasitic endectocide clinically used for onchocerciasis and lymphatic filariasis control at single doses of 150 to 200 mcg/kg. It also shortens the lifespan of mosquitoes that feed on individuals recently treated with ivermectin. However, the effect after a 150 to 200 mcg/kg oral dose is short-lived (6 to 11 days). Modeling suggests higher doses, which prolong the mosquitocidal effects, are needed to make a significant contribution to malaria elimination. Ivermectin has a wide therapeutic index and previous studies have shown doses up to 2000 mcg/kg (ie, 10 times the US Food and Drug Administration approved dose) are well tolerated and safe; the highest dose used for onchocerciasis is a single dose of 800 mcg/kg.ObjectiveThe aim of this study is to determine the safety, tolerability, and efficacy of ivermectin doses of 0, 300, and 600 mcg/kg/day for 3 days, when provided with a standard 3-day course of the antimalarial dihydroartemisinin-piperaquine (DP), on mosquito survival.MethodsThis is a double-blind, randomized, placebo-controlled, parallel-group, 3-arm, dose-finding trial in adults with uncomplicated malaria. Monte Carlo simulations based on pharmacokinetic modeling were performed to determine the optimum dosing regimens to be tested. Modeling showed that a 3-day regimen of 600 mcg/kg/day achieved similar median (5 to 95 percentiles) maximum drug concentrations (Cmax) of ivermectin to a single of dose of 800 mcg/kg, while increasing the median time above the lethal concentration 50% (LC50, 16 ng/mL) from 1.9 days (1.0 to 5.7) to 6.8 (3.8 to 13.4) days. The 300 mcg/kg/day dose was chosen at 50% of the higher dose to allow evaluation of the dose response. Mosquito survival will be assessed daily up to 28 days in laboratory-reared Anopheles gambiae s.s. populations fed on patients' blood taken at days 0, 2 (Cmax), 7 (primary outcome), 10, 14, 21, and 28 after the start of treatment. Safety outcomes include QT-prolongation and mydriasis. The trial will be conducted in 6 health facilities in western Kenya and requires a sample size of 141 participants (47 per arm). Sub-studies include (1) rich pharmacokinetics and (2) direct skin versus membrane feeding assays.ResultsRecruitment started July 20, 2015. Data collection was completed July 2, 2016. Unblinding and analysis will commence once the database has been completed, cleaned, and locked.ConclusionsHigh-dose ivermectin, if found to be safe and well tolerated, might offer a promising new tool for malaria elimination.

Dataset Information

Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial.

Publications

Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial.

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