Efficacy of Nilotinib in Patients With Moderately Advanced Parkinson Disease: A Randomized Clinical Trial.

Importance: There is a critical need for careful and independent validation of reported symptomatic efficacy and dopaminergic biomarker changes induced by nilotinib in Parkinson disease (PD). Objectives: To assess safety and tolerability of nilotinib in participants with moderately advanced PD. Secondary and exploratory objectives were to assess its affect on PD disability, pharmacokinetics, cerebrospinal fluid (CSF) penetration, and biomarkers. Design, Setting, and Participants: This was a 6-month, multicenter, randomized parallel-group, double-blind, placebo-controlled trial. Recruitment was from November 20, 2017, to December 28, 2018, and follow-up ended on September 9, 2019. The study was conducted at 25 US sites. The study approached 173 patients, of whom 48 declined, 125 were screened, and 76 who received a stable regimen of PD medications were enrolled (39% screen failure). Interventions: Participants were randomized 1:1:1 to placebo, 150-mg nilotinib, or 300-mg nilotinib once daily orally for 6 months, followed by 2-month off-drug evaluation. Main Outcomes and Measures: The primary outcomes were safety and tolerability. The tolerability end point was defined as the ability to complete the study while receiving the assigned dose. An active arm was considered tolerable if the percentage of participants meeting the tolerability end point for that group was not significantly lower than the percentage observed in the placebo group. Secondary outcomes included change in PD disability (Movement Disorder Society Unified Parkinson's Disease Rating Scale [MDS-UPDRS], Part II OFF/ON). Exploratory outcomes included serum and CSF pharmacokinetic profile, and CSF dopaminergic biomarkers. Results: At baseline, mean (SD) participants' age was 64.6 (7.5) years, 52 were male (68%), mean (SD) disease duration was 9.9 years (4.7), MDS-UPDRS Part 1-3 OFF score was 66.4 (19.3), ON score was 48.4 (16.2), and Montreal Cognitive Assessment score was 27.1 (2.2). The number of participants who completed the study receiving the assigned dose were 21 (84%), 19 (76%), and 20 (77%) in the placebo, 150-mg, and 300-mg arms, respectively. Both active doses had acceptable safety profile. The most common reasons for drug suspension were asymptomatic, dose-dependent elevations of amylase, and/or lipase. Nilotinib, 150 mg and 300 mg, exhibited worse MDS-UPDRS-3 ON scores compared with placebo, achieving significance for nilotinib, 300 mg, at month 1 (P < .01). There was no difference in the change of MDS-UPDRS-3 OFF from baseline to 6 months between groups (P = .17). Cerebrospinal fluid/serum ratio of nilotinib concentration was 0.2% to 0.3%. There was no evidence of treatment-related alteration of dopamine metabolites in the CSF. Conclusions and Relevance: While we demonstrated acceptable safety and tolerability of nilotinib in our cohort, the low CSF exposure and lack of biomarkers effect combined with the efficacy data trending in the negative direction indicate that nilotinib should not be further tested in PD. Trial Registration: ClinicalTrials.gov Identifier: NCT03205488.

Seven-Year Experience From the National Institute of Neurological Disorders and Stroke-Supported Network for Excellence in Neuroscience Clinical Trials.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings. Conclusions and Relevance: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.

Can Probiotics Improve Your Surgical Outcomes?

Despite ongoing advances in medical technology, postoperative infections and infectious complications continue to be a significant cause of morbidity and mortality. Surgical trauma and prophylactic antibiotics disrupt the balance of the intestinal microbiota and barrier function of the gut, potentiating an enhanced inflammatory response and further immune system depression. With the increasing costs of health care and emergence of multidrug-resistant bacteria, alternative approaches must be explored. Many clinical studies have demonstrated that the use of probiotics, prebiotics, or a combination of both (synbiotics) as a part of innovative strategies can improve outcomes of elective abdominal and gastrointestinal surgical procedures. It has been demonstrated that probiotics play a role in gut barrier improvement and immunomodulation. However, it is evident that additional research is needed including larger, multicenter, randomized controlled trials to validate the safety and efficacy of their use in surgical patients. The purpose of this article is to discuss background of probiotic use in abdominal/gastrointestinal surgery, risk and benefits, clinical relevance for health care providers, and further implications for research.

Renal function following fistulography in patients with advanced chronic kidney disease.

BACKGROUND/AIMS: Contrast-induced acute kidney injury (CIAKI) is associated with an accelerated progression of underlying chronic kidney disease (CKD). We sought to characterize the rate of loss of kidney function following fistulography in patients with advanced CKD. MATERIALS/METHODS: We identified all patients with stage 4 or 5 non-dialysis-dependent CKD who underwent fistulography with iodinated contrast for non-maturing arteriovenous fistulae between 1 January 2010 and 30 November 2011. We recorded all eGFR values measured during the 6 months prior to and 6 months following the procedure, the volume and type of contrast, use of intravenous fluid and N-acetylcysteine (NAC), and timing of dialysis initiation following the procedure. We used mixed linear regression with random effects to compare the composite slope of decline in eGFR prior to and following fistulography. RESULTS: Overall, 27 patients underwent a total of 44 fistulograms. The mean age of the patients was 66 years and mean baseline eGFR was 16.7 ± 5 mL/min/1.73 m(2). Patients received a median volume of contrast of 12 mL [IQR 10-20]. None of the patients initiated acute dialysis within weeks following the procedure. In unadjusted analyses, there was no statistically significant change in the rate of decline in eGFR following fistulography compared to pre-procedure (0.14 mL/min/month versus -0.14 mL/min/month, p = 0.11). In analyses that adjusted for procedural, demographic and clinical variables, the decline in eGFR following fistulography was not statistically different than before the procedure (0.15 mL/min/month versus -0.14 mL/min/month, p = 0.11). CONCLUSIONS: Fistulography with small volumes of iodinated contrast in patients with advanced CKD does not result in more rapid progression of underlying CKD.

Involvement of p21cip1/waf1 in the anti-proliferative effects of polyethylene glycol in colon carcinogenesis.

Polyethylene glycol (PEG) is a safe and effective chemopreventive agent against colorectal carcinogenesis in cell culture, animal models and human subjects. Although the precise molecular mechanism is unclear, we previously reported that PEG suppresses colonic epithelial proliferation. As cellular proliferation is driven by complex G1-S phase transition, we now characterize the role of PEG on cell cycle regulation. We focused our attention on the effect of PEG on the CDK inhibitor p21cip1/waf1, which is implicated in early colon carcinogenesis and is upregulated by non-steroidal anti-inflammatory drugs. These studies were done in the azoxymethane-treated (AOM) rat model as well as in HT-29 colon cancer cells. Immunohistochemical analysis revealed that while AOM decreased the p21 expression (75%, p<0.01) in the premalignant colonic mucosa, PEG induced p21 levels back to normal. These findings paralleled a decreased BrdUrd incorporation (78%, p<0.001) and hypophosphorylated retinoblastoma protein (Rb; by 47%) signifying PEG's antiproliferative activity. Furthermore, in HT-29 cells, PEG decreased proliferation as measured by PCNA (68% reduction), increased p21 expression (2.3-fold), induced cell cycle arrest during G0/G1 phase (45% reduction in S phase cells) and inhibited the phosphorylation of Rb (by 52% compared to untreated). PEG caused greater than a 2-fold induction of protein and mRNA level of p21cip1/waf1 in HT-29 cells. These results demonstrate for the first time that PEG is involved in p21 regulation concomitant with G1S phase cell cycle arrest and it is through these effects that it can exert its anti-proliferative and hence chemopreventive role.