A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment.

The locus coeruleus is the initial site of Alzheimer's disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer's pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer's disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer's disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-ß42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-ß42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer's disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer's disease progression.

Every 2-month belatacept maintenance therapy in kidney transplant recipients greater than 1-year posttransplant: A randomized, noninferiority trial.

Belatacept results in improved kidney transplant outcomes, but utilization has been limited by logistical barriers related to monthly (q1m) intravenous infusions. Every 2-month (q2m) belatacept has potential to increase utilization, therefore we conducted a randomized noninferiority trial in low immunologic risk renal transplant recipients greater than 1-year posttransplant. Patients on belatacept were randomly assigned to q1m or q2m therapy. The primary objective was a noninferiority comparison of renal function (eGFR) at 12 months with a noninferiority margin (NIM) of 6.0 ml/min/1.73 m2 . One hundred and sixty-six participants were randomized to q1m (n = 82) or q2m (n = 84) belatacept, 163 patients received treatment, and 76 q1m and 77 q2m subjects completed the 12-month study period. Every 2-month belatacept was noninferior to q1m, as the difference in mean eGFR adjusted for baseline renal function did not exceed the NIM. Two-month dosing was safe and well tolerated, with no patient deaths or graft losses. Four rejection episodes and three cases of donor-specific antibodies (DSAs) occurred among q2m subjects; however, only one rejection and one instance of DSA were observed in subjects adherent to the study protocol. Every 2-month belatacept therapy may facilitate long-term utilization of costimulation blockade, but future multicenter studies with long-term follow-up will further elucidate immunologic risk. (ClinicalTrials.gov NCT02560558).

Bolus Weekly Vitamin D3 Supplementation Impacts Gut and Airway Microbiota in Adults With Cystic Fibrosis: A Double-Blind, Randomized, Placebo-Controlled Clinical Trial.

Context: Disruption of gut microbiota may exacerbate severity of cystic fibrosis (CF). Vitamin D deficiency is a common comorbidity in patients with CF that may influence composition of the gut microbiota. Objectives: Compare microbiota of vitamin D-sufficient and -insufficient CF patients and assess impact of a weekly high-dose vitamin D3 bolus regimen on gut and airway microbiome in adults with CF and vitamin D insufficiency (25-hydroxyvitamin D < 30 ng/mL). Design: Forty-one subjects with CF were classified into two groups: vitamin D insufficient (n = 23) and vitamin D sufficient (n = 18). Subjects with vitamin D insufficiency were randomized to receive 50,000 IU of oral vitamin D3 or placebo weekly for 12 weeks. Sputum and stool samples were obtained pre- and postintervention and 16S ribosomal RNA genes sequenced using Illumina MiSeq technology. Results: Gut microbiota differed significantly based on vitamin D status with Gammaproteobacteria, which contain numerous, potentially pathogenic species enriched in the vitamin D-insufficient group. Principal coordinates analysis showed differential gut microbiota composition within the vitamin D-insufficient patients following 12 weeks treatment with placebo or vitamin D3 (permutation multivariate analysis of variance = 0.024), with Lactococcus significantly enriched in subjects treated with vitamin D3, whereas Veillonella and Erysipelotrichaceae were significantly enriched in patients treated with placebo. Conclusion: This exploratory study suggests that vitamin D insufficiency is associated with alterations in microbiota composition that may promote inflammation and that supplementation with vitamin D has the potential to impact microbiota composition. Additional studies to determine the impact of vitamin D on microbiota benefit clinical outcomes in CF are warranted.

A phase II trial of ISIS 3521 in patients with metastatic colorectal cancer.

This phase II study was designed to characterize the clinical activity of ISIS 3521 in patients with metastatic colorectal cancer (CRC). Sixteen patients with pretreated or refractory CRC were treated with ISIS 3521. Eleven patients were given a dose of 2.0 mg/kg per day, and 5 patients received 3.0 mg/kg per day given over 21 days followed by a 7-day rest period. Patients continued with study until evidence of disease progression or unacceptable toxicity was detected. Patients underwent baseline tumor biopsies followed by a second biopsy during the last week of the first 21-day infusion. All 16 patients underwent baseline tumor biopsies, and 12 of the 16 patients underwent on-study tumor biopsies. No evidence of tumor response was observed. One patient had stable disease after 2 cycles and remained on for 1 additional cycle only to demonstrate progression of disease at that time. No dose-limiting or other significant toxicities were observed at both dosages, which could not be explained by progression of disease. Fatigue was common in all patients treated but was not dose limiting, and there was no evidence of coagulopathy. Analysis of the tumor biopsies obtained from the 11 evaluable samples showed marked uptake of ISIS 3521 in the normal liver parenchyma. However, there was minimal uptake within the tumor cells. In addition, no evidence of any alteration in protein kinase C-a within the tumors or any downstream effects leading to apoptosis were observed. ISIS 3521 demonstrated no clinical activity or target modulation in refractory metastatic CRC.