Five Year Outcomes in Patients with End Stage Renal Disease Who Received a Bioengineered Human Acellular Vessel for Dialysis Access.

OBJECTIVE: Patients with end stage renal failure who require haemodialysis suffer morbidity and mortality due to vascular access. Bioengineered human acellular vessels (HAVs) may provide a haemodialysis access option with fewer complications than other grafts. In a prospective phase II trial from 2012 to 2014 (NCT01744418), HAVs were implanted into 40 haemodialysis patients at three sites in Poland. The trial protocol for this "first in man" use of the HAV contemplated only two years of follow up, and the trial results were initially reported in 2016. In light of the retained HAV function seen in many of the patients at the two year time point, follow up for patients who were still alive was extended to a total of 10 years. This interim follow up report, at the long term time point of five years, assessed patient and conduit status in those who continued routine dialysis with the HAV. METHODS: HAVs are bioengineered by culturing human vascular smooth muscle cells on a biodegradable polymer matrix. In this study, patients with patent HAV implants at 24 months were followed every three months, starting at month 27 through to month 60, or at least five years post-implantation. This report contains the follow up functional and histological data on 29 of the original 40 patients who demonstrated HAV function at the 24 month time point. RESULTS: Eleven patients completed at month 60. One patient maintained primary patency, and 10 maintained secondary patency. Secondary patency was estimated at 58.2% (95% confidence interval 39.2-73.1) at five years, after censoring for deaths (n = 8) and withdrawals (n = 1). No HAV conduit infections were reported during the follow up period. CONCLUSION: This phase II long term follow up shows that the human acellular vessel (HAV) may provide durable and functional haemodialysis access for patients with end stage renal disease.

Arterial reconstruction with human bioengineered acellular blood vessels in patients with peripheral arterial disease.

OBJECTIVE: Vascular conduit is essential for arterial reconstruction for a number of conditions, including trauma and atherosclerotic occlusive disease. We have developed a tissue-engineered human acellular vessel (HAV) that can be manufactured, stored on site at hospitals, and be immediately available for arterial vascular reconstruction. Although the HAV is acellular when implanted, extensive preclinical and clinical testing has demonstrated that the HAV subsequently repopulates with the recipient's own vascular cells. We report a first-in-man clinical experience using the HAV for arterial reconstruction in patients with symptomatic peripheral arterial disease. METHODS: HAVs were manufactured using human vascular smooth muscle cells grown on a biodegradable scaffold. After the establishment of adequate cell growth and extracellular matrix deposition, the vessels were decellularized to remove human cellular antigens. Manufactured vessels were implanted in 20 patients with symptomatic peripheral arterial disease as above-knee, femoral-to-popliteal arterial bypass conduits. After HAV implantation, all patients were assessed for safety, HAV durability, freedom from conduit infection, and bypass patency for 2 years. RESULTS: Twenty HAVs were placed in the arterial, above-knee, femoral-to-popliteal position in patients with rest pain (n = 3) or symptomatic claudication (n = 17). All HAVs functioned as intended and had no evidence of structural failure or rejection by the recipient. No acute HAV infections were reported, but three surgical site infections were documented during the study period. Three non-HAV-related deaths were reported. One vessel developed a pseudoaneurysm after suspected iatrogenic injury during a balloon thrombectomy. No amputations of the HAV implanted limb occurred over the 2-year period, and no HAV infections were reported in approximately 34 patient-years of continuous patient follow-up. CONCLUSIONS: Human tissue engineered blood vessels can be manufactured and readily available for peripheral arterial bypass surgery. Early clinical experience with these vessels, in the arterial position, suggest that they are safe, have acceptable patency, a low incidence of infection, and do not require the harvest of autologous vein or any cells from the recipient. Histologic examination of tissue biopsies revealed vascular remodeling and repopulation by host cells. This first-in-man arterial bypass study supports the continued development of human tissue engineered blood vessels for arterial reconstruction, and potential future expansion to clinical indications including vascular trauma and repair of other size-appropriate peripheral arteries.

Patency of ePTFE Arteriovenous Graft Placements in Hemodialysis Patients: Systematic Literature Review and Meta-Analysis.

Arteriovenous grafts (AVGs) are an appropriate option for vascular access in certain hemodialysis patients. Expanded polytetrafluoroethylene (ePTFE) has become the dominant material for such grafts, due in part to innovations in graft design and surgical interventions to reduce complications and improve patency rates. Comprehensive evidence syntheses have not been conducted to update AVG performance in an era in which both access choice and ePTFE graft functioning may have changed. We conducted a systematic review and meta-analysis summarizing outcomes from recent studies of ePTFE AVGs in hemodialysis, following PRISMA standards. Literature searches were conducted in multiple databases to identify observational and interventional studies of AVG patency and infection risk. Primary, primary-assisted, and secondary patency rates were analyzed at 6, 12, 18, and 24 months postplacement. Kaplan-Meier graft survival plots were digitized to recreate individual patient-level data. Patency rates were pooled using a random effects model. We identified 32 studies meeting our selection criteria that were published from 2004 through 2019. A total of 38 study arms of ePTFE grafts were included, representing 3381 AVG accesses placed. The mean primary, primary-assisted, and secondary patency rates at 1 year were 41% (95% CI, 35% to 47%), 46% (95% CI, 41% to 51%), and 70% (95% CI, 64% to 75%), respectively. Mean 24-month patency rates were 28% (95% CI, 22% to 33%), 34% (95% CI, 27% to 41%), and 54% (95% CI, 47% to 61%), respectively. A high degree of heterogeneity across studies was observed. Overall risk of infection was not consistently reported, but among available studies the pooled estimate was 9% per patient-year (95% CI, 6% to 12%). This meta-analysis provides an up-to-date estimate of the performance of ePTFE AVGs, within the context of improved graft designs and improved interventional techniques.

Bioengineered human acellular vessels for dialysis access in patients with end-stage renal disease: two phase 2 single-arm trials.

BACKGROUND: For patients with end-stage renal disease who are not candidates for fistula, dialysis access grafts are the best option for chronic haemodialysis. However, polytetrafluoroethylene arteriovenous grafts are prone to thrombosis, infection, and intimal hyperplasia at the venous anastomosis. We developed and tested a bioengineered human acellular vessel as a potential solution to these limitations in dialysis access. METHODS: We did two single-arm phase 2 trials at six centres in the USA and Poland. We enrolled adults with end-stage renal disease. A novel bioengineered human acellular vessel was implanted into the arms of patients for haemodialysis access. Primary endpoints were safety (freedom from immune response or infection, aneurysm, or mechanical failure, and incidence of adverse events), and efficacy as assessed by primary, primary assisted, and secondary patencies at 6 months. All patients were followed up for at least 1 year, or had a censoring event. These trials are registered with ClinicalTrials.gov, NCT01744418 and NCT01840956. FINDINGS: Human acellular vessels were implanted into 60 patients. Mean follow-up was 16 months (SD 7·6). One vessel became infected during 82 patient-years of follow-up. The vessels had no dilatation and rarely had post-cannulation bleeding. At 6 months, 63% (95% CI 47-72) of patients had primary patency, 73% (57-81) had primary assisted patency, and 97% (85-98) had secondary patency, with most loss of primary patency because of thrombosis. At 12 months, 28% (17-40) had primary patency, 38% (26-51) had primary assisted patency, and 89% (74-93) had secondary patency. INTERPRETATION: Bioengineered human acellular vessels seem to provide safe and functional haemodialysis access, and warrant further study in randomised controlled trials. FUNDING: Humacyte and US National Institutes of Health.

Efficacy and tolerability of lasmiditan, an oral 5-HT(1F) receptor agonist, for the acute treatment of migraine: a phase 2 randomised, placebo-controlled, parallel-group, dose-ranging study.

BACKGROUND: Lasmiditan (COL-144) is a novel, centrally acting, highly selective 5-HT(1F) receptor agonist without vasoconstrictor activity that seemed effective when given as an intravenous infusion in a proof-of-concept migraine study. We aimed to assess the efficacy and safety of oral lasmiditan for the acute treatment of migraine. METHODS: In this multicentre, double-blind, parallel-group, dose-ranging study in 43 headache centres in five European countries, patients with migraine with and without aura and who were not using prophylaxis were randomly assigned (1:1:1:1:1) to treat one moderate or severe attack at home with 50 mg, 100 mg, 200 mg, or 400 mg lasmiditan, or placebo. Study drug and placebo were supplied in identical numbered tablet packs. The randomisation code was generated by an independent statistician. Patients and investigators were masked to treatment allocation. The primary endpoint was dose response for headache relief (moderate or severe becoming mild or none) at 2 h. The primary analysis was done in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00883051. FINDINGS: Between July 8 2009, and Feb 18, 2010, 512 patients were randomly assigned to treatment, 391 of whom received treatment. 86 patients received placebo (81 included in primary analysis) and 305 received lasmiditan (50 mg n=79, 100 mg n=81, 200 mg n=69, and 400 mg n=68 included in primary analysis). There was a linear association between headache response rate at 2 h and lasmiditan dose (Cochran-Armitage test p<0·0001). Every lasmiditan treatment dose significantly improved headache response at 2 h compared with placebo (lasmiditan 50 mg: difference 17·9%, 95% CI 3·9-32·1, p=0·022; 100 mg: 38·2%, 24·1-52·4, p<0·0001; 200 mg: 28·8%, 9·6-39·9, p=0·0018; 400 mg: 38·7%, 23·9-53·6, p<0·0001). The proportion of patients with treatment-emergent adverse events increased with increasing doses (53/82 [65%], 59/82 [72%], 61/71 [86%], and 59/70 [84%] for lasmiditan 50, 100, 200, and 400 mg, respectively vs 19/86 [22%] for placebo). Most adverse events were mild or moderate in intensity, with 16 of 82 (20%), 23 of 82 (28%), 28 of 71 (39%), and 31 of 70 (44%) of patients on lasmiditan 50, 100, 200, and 400 mg, respectively reporting a severe adverse event compared with five of 86 (6%) on placebo. The most common adverse events were CNS related and included dizziness, fatigue, vertigo, paraesthesia, and somnolence. INTERPRETATION: Oral lasmiditan seems to be safe and effective in the acute treatment of migraine. Further assessment in larger placebo-controlled and triptan-controlled trials are needed to assess the potential role of lasmiditan in acute migraine therapy. FUNDING: CoLucid Pharmaceuticals.

Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan--a randomised proof-of-concept trial.

INTRODUCTION: Lasmiditan (COL-144; LY573144) is a novel, highly selective and potent agonist at 5-HT(1F) receptors that lacks vasoconstrictor activity. Preclinical and early clinical experiments predict acute antimigraine efficacy of COL-144 that is mediated through a non-vascular, primarily neural, mechanism. SUBJECTS AND METHODS: In a randomised, multicentre, placebo-controlled, double-blind, group-sequential, adaptive treatment-assignment, proof-of-concept and dose-finding study, we treated 130 subjects in-hospital during a migraine attack. Subjects were allocated to an intravenous dose level of lasmiditan or placebo in small cohorts. The starting dose was 2.5 mg. Subsequent doses were adjusted, up or down, according to the safety and efficacy seen in the preceding cohort. The primary outcome measure was headache response defined as improvement from moderate or severe headache at baseline to mild or no headache at 2 h post-dose. The study was designed to explore the overall dose response relationship but was not powered to differentiate individual doses from placebo, nor to detect effect differences for other migraine symptoms. RESULTS: Forty-two subjects received placebo and 88 received lasmiditan in doses of 2.5-45 mg. Subjects were observed in the clinic for 4 h after treatment and used a diary card to record symptoms and adverse events for up to 24 h. The study was terminated when the 20 mg dose met predefined efficacy stopping rules. Of subjects treated in the 10, 20, 30 and 45 mg lasmiditan dose groups, 54-75% showed a 2 h headache response, compared to 45% in the placebo group (P = 0.0126 for the linear association between response rates and dose levels). Patient global impression at 2 h and lack of need for rescue medication also showed statistically significant linear correlations with dose. Lasmiditan was generally well tolerated. Adverse events were reported by 65% of subjects on lasmiditan and by 43% on placebo and were generally mild. Dizziness, paresthesia and sensations of heaviness (usually limb) were more common on lasmiditan. CONCLUSIONS: At intravenous doses of 20 mg and higher, lasmiditan proved effective in the acute treatment of migraine. Further studies to assess the optimal oral dose and full efficacy and tolerability profile are under way. The non-vascular, neural mechanism of action of lasmiditan may offer an alternative means to treat migraine especially in patients who have contra-indications for agents with vasoconstrictor activity. The clinicaltrials.gov identifier for this study is NCT00384774.