Significant Changes In Vital Signs Research Articles

The clinical population pharmacokinetics, metabolomics and therapeutic analysis of alkaloids from Alstonia scholaris leaves in acute bronchitis patients

BackgroundCapsule of alkaloids from leaf of Alstonia scholaris (CALAS) is a new investigational botanical drug (No. 2011L01436) for respiratory disease. Clinical population pharmacokinetics (PK), metabolomics and therapeutic data are essential to guide dosing in patients. Previous research has demonstrated the potential therapeutic effect of CALAS on acute bronchitis. Further clinical trial data are needed to verify its clinical efficacy, pharmacokinetics behavior, and influence of dosage and other factors. PurposeTo verify the clinical efficacy and explore the potential biomarkers related to CALAS treatment for acute bronchitis. Materials and Methods: Oral CALAS was assessed in a randomized, double-blind, placebo-controlled trial. Fifty-five eligible patients were randomly assigned to four cohorts to receive 20, 40 or 80 mg, of CALAS three times daily for seven days, or placebo. Each CALAS cohort included 15 subjects, and the placebo group included 10 subjects. A population PK model of CALAS was developed using plasma with four major alkaloid components. Metabolomics analysis was performed to identify biomarkers correlated with the therapeutic effect of CALAS, and efficacy and safety were assessed based on clinical symptoms and adverse events. ResultsThe symptoms of acute bronchitis were alleviated by CALAS treatment without serious adverse events or clinically significant changes in vital signs, electrocardiography or upper abdominal Doppler ultrasonography. Moreover, one compartment model with first-order absorption showed that an increase in aspartate transaminase will reduce the clearance (CL) of scholaricine, and picrinine CL was inversely proportional to body mass index, while 19-epischolaricine and vallesamine CL increased with aging. The serum samples from acute bronchitis patients at different time points were analyzed using UPLC-QTOF in combination with the orthogonal projection to latent structures-discriminant analysis, which indicated higher levels of lysophosphatidylcholines, lysophosphatidylethanolamines and amino acids with CALAS treatment than with placebo. ConclusionThis is the first study to evaluate the clinical efficacy and explored the potential biomarkers related to CALAS therapeutic mechanism of acute bronchitis by means of clinical trial combined the metabolomics study. This exploratory study provides a basis for further research on clinical efficacy and optimal dosing regimens based on pharmacokinetics behavior. Additional acute bronchitis patients and CALAS PK samples collected in future studies may be used to improve model performance and maximize its clinical value.

S119: PRELIMINARY RESULTS OF A PHASE 1 STUDY IN HEALTHY SUBJECTS ADMINISTERED INCLACUMAB, A FULLY HUMAN IGG4 ANTI-P-SELECTIN MONOCLONAL ANTIBODY IN DEVELOPMENT FOR TREATMENT OF SICKLE CELL DISEASE

Background: Inclacumab, a fully human IgG4 anti-P-selectin monoclonal antibody, is being developed for the reduction of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). P-selectin-mediated platelet-leukocyte aggregate (PLA) formation has been shown to contribute to vaso-occlusion. Safety and pharmacology of inclacumab have previously been well characterized in over 700 subjects (healthy volunteers and patients with cardiovascular disease), at doses up to 20 mg/kg every 4 weeks for up to 9 months. The current Phase 1 study was initiated to evaluate the safety and pharmacology of inclacumab at doses of 20 mg/kg and 40 mg/kg in healthy subjects in support of a target Phase 3 dose of 30 mg/kg administered every 12 weeks to patients with SCD. Methods: Healthy adult subjects over 18 years of age without significant current or prior health conditions received a single intravenous (IV) dose of 20 mg/kg inclacumab infused over approximately one hour (Cohort 1). Following a review of safety, a second cohort received a single IV dose of 40 mg/kg infused over approximately one hour (Cohort 2). The total study duration and sample collection period was 29 weeks. Final safety and preliminary pharmacokinetics (PK), anti-drug antibody (ADA), and ex vivo thrombin receptor-activating peptide (TRAP)-activated PLA formation data are reported. Results: Fifteen subjects received a single dose of inclacumab 20 mg/kg (n=6) or 40 mg/kg (n=9). Median age was 42 years (range 22–52 years); median body weight was 73.6 kg (range 63.7–89.3 kg). Through the prespecified 72-hour post-infusion safety assessment period in both cohorts, no treatment-emergent adverse events (AEs) > grade 1 (mild) nor dose-limiting toxicities were reported. Across the duration of the study, there were no serious AEs, infusion-related reactions, or hypersensitivity reactions. Additionally, no clinically significant changes in vital signs, laboratory findings, or ECGs were observed. The most common AEs were upper respiratory tract infections, headache, myalgia, back pain, and contact dermatitis. The only events assessed by the investigator as potentially related to inclacumab were headache and dizziness, which were experienced by one subject (20 mg/kg) and occurred 4 hours following the end of infusion. In healthy subjects, inclacumab demonstrated dose-proportional PK over the dose range tested; PK parameter estimates were consistent with those reported for monoclonal antibodies. Geometric mean Cmax following single doses of 20 and 40 mg/kg were 402 and 970 µg/mL, respectively. Mean TRAP-activated pre-dose PLA formation was 33–39% across cohorts and decreased to 9–14% at 2 hours following end of infusion. PLA inhibition was sustained up to 23 weeks for both the 20 and 40 mg/kg doses. Two subjects in the 40 mg/kg cohort were ADA-positive on Week 12 and thereafter; a preliminary analysis demonstrated no apparent impact on PK or safety in these subjects. Conclusions: Inclacumab displayed a well-tolerated safety profile for up to 29 weeks following a single dose of 20 or 40 mg/kg in healthy subjects. Durable inhibition of TRAP-activated PLA formation was observed up to 23 weeks. Overall, the results support a Phase 3 dose of 30 mg/kg every 12 weeks in patients with SCD-related VOCs. Funding: This study was supported by Global Blood Therapeutics.

Clinical Validation of BCI-Controlled Wheelchairs in Subjects With Severe Spinal Cord Injury.

Brain-controlled wheelchairs are one of the most promising applications that can help people gain mobility after their normal interaction pathways have been compromised by neuromuscular diseases. The feasibility of using brain signals to control wheelchairs has been well demonstrated by healthy people in previous studies. However, most potential users of brain-controlled wheelchairs are people suffering from severe physical disabilities or who are in a "locked-in" state. To further validate the clinical practicability of our previously proposed P300-based brain-controlled wheelchair, in this study, 10 subjects with severe spinal cord injuries participated in three experiments and completed ten predefined tasks in each experiment. The average accuracy and information transfer rate (ITR) were 94.8% and 4.2 bits/min, respectively. Moreover, we evaluated the physiological and cognitive burdens experienced by these individuals before and after the experiments. There were no significant changes in vital signs during the experiment, indicating minimal physiological and cognitive burden. The patients' average systolic blood pressure before and after the experiment was 113±13.7 mmHg and 114±11.9 mmHg, respectively (P = 0.122). The patients' average heart rates before and after the experiment were 79±8.4/min and 79±8.2/min, respectively (P = 0.147). The average task load, measured by the National Aeronautics and Space Administration task load index, ranged from 10.0 to 25.5. The results suggest that the proposed P300-based brain-controlled wheelchair is safe and reliable; additionally, it does not significantly increase the patient's physical and mental task burden, demonstrating its potential value in clinical applications. Our study promotes the development of a more practical brain-controlled wheelchair system.

Clinical trial and therapeutical progress of COVID-19 treated with remdesivir: A review

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that first reported in Wuhan City, China. Most confirmed cases of COVID-19 develop mild, moderate, severe to critical symptoms. One of the therapies given and of concern is remdesivir. Remdesivir is an antiviral with a broad spectrum that has activity against various types of viruses including Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV. The aim of this review was to evaluate the clinical trial and the therapeutical progress of remdesivir in the treatment of COVID-19 patients. Databases used for this review were Google Scholar, JAMA, PubMed and Science Direct library. The inclusion criteria were covering any literature using remdesivir in clinical studies and COVID-19 therapy published from December 2019 to October 2020. Overall no pattern of laboratory abnormalities and clinically significant changes in vital signs or ECG shifts was observed in patients receiving remdesivir. The decision to use remdesivir in COVID-19 treatment should consider its potential benefits and risks.

Recombinant ADAMTS13 for Patients with Severe Congenital Thrombotic Thrombocytopenic Purpura: Design of a Phase 3b Open-Label Continuation Study of Prophylactic and on-Demand Treatment

BackgroundCongenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare and potentially life-threatening autosomal recessive inherited thrombotic microangiopathy with an estimated prevalence of <1 in 1 million people. cTTP is caused by a deficiency of the metalloprotease ADAMTS13. Although patients can receive replacement therapy with infusions of either fresh-frozen or solvent/detergent-treated plasma, the level of ADAMTS13 that can be achieved is restricted by infusion volume, and patients can also experience adverse reactions to plasma infusions. A recombinant ADAMTS13 (rADAMTS13; TAK-755; Takeda Development Center Americas, Inc., Lexington, MA, USA) is being developed for use as a replacement therapy for patients with cTTP. A phase 1 study (NCT02216084) in patients with severe cTTP has shown the pharmacokinetic (PK) parameters of rADAMTS13 to be comparable with those estimated in previous plasma infusion studies. A phase 3 study (NCT03393975) to assess the safety and efficacy of rADAMTS13 in patients with severe cTTP was initiated in October 2017 and is ongoing. Here, we report the design of a continuation study, which follows on from the phase 3 study.Study Design and MethodsThis is a phase 3b, prospective, open-label, multicenter, single-arm continuation study (NCT04683003) to evaluate the long-term safety and efficacy of rADAMTS13 for prophylactic and on-demand treatment in patients with severe cTTP. The study will enroll approximately 77 patients and include approximately 57 patients who completed the phase 3 study (48 patients from the prophylaxis cohort; 9 patients from the on-demand cohort) and at least 20 patients who are naïve to rADAMTS13. Patients from expanded access programs or who had an allergic reaction to prophylactic standard of care therapy in the phase 3 study are also eligible for enrollment. Patients who were 0 to 70 years of age at screening for either the phase 3 study or the continuation study and were diagnosed with severe congenital ADAMTS13 deficiency (ADAMTS13 activity <10%) are eligible for inclusion. Patients will be excluded if they have a known life-threatening hypersensitivity to any constituents of rADAMTS13 or have functional ADAMTS13 inhibitors at screening. Patients will be enrolled into either the prophylaxis or on-demand cohort depending on their current therapy and physician consultations (Figure). Patients who completed the phase 3 study and those naïve to rADAMTS13 treatment who are enrolled in the prophylaxis cohort will receive 40 IU/kg rADAMTS13 intravenous infusions either once a week (Q1W) or once every 2 weeks (Q2W). Patients in the prophylaxis cohort can opt to receive at-home rADAMTS13 infusions and will be required to attend interval study visits every 12 weeks. Patients experiencing an acute TTP event will be enrolled in the on-demand cohort and receive 40 IU/kg rADAMTS13 on day 1, 20 IU/kg on day 2, and 15-IU/kg infusions daily from day 3 until 2 days after resolution of the acute event; patients can then choose to move into the prophylaxis cohort or discontinue from the study. Patients in the prophylaxis cohort who experience an acute TTP event during the study will also receive rADAMTS13 in the same dosing regimen as the on-demand cohort (Figure). The primary objective is to evaluate the long-term safety and tolerability of rADAMTS13, measured by the incidence of related treatment-emergent adverse events and serious adverse events, as well as clinically significant changes in vital signs, clinical chemistry, and hematology. The efficacy of rADAMTS13 prophylaxis is a secondary objective of the study, as is the incidence of isolated TTP manifestations. Other secondary outcomes include immunogenicity, health-related quality of life, and healthcare resource utilization in both the prophylaxis and on-demand cohorts. PK and pharmacodynamic parameters of rADAMTS13 will also be assessed. Patient participation is estimated to be either up to 3 years in duration or dependent on the commercial availability of rADAMTS13 in the respective country. The study was initiated in April 2021; estimated completion is September 2026.ConclusionTreatment options for cTTP are limited. This study will evaluate the long-term safety and efficacy of rADAMTS13 for the treatment of patients with severe cTTP. [Display omitted] DisclosuresJain: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc.,: Current Employment. Marquez: Takeda Development Center Americas, Inc.,: Current Employment; Takeda: Current equity holder in publicly-traded company. Martell: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc.,: Current Employment.

Preliminary Results of a Phase 1 Study in Healthy Subjects Administered Inclacumab, a Fully Human IgG4 Anti-P-Selectin Monoclonal Antibody in Development for Treatment of Sickle Cell Disease

Background: Inclacumab, a fully human IgG4 anti-P-selectin monoclonal antibody, is being developed for the reduction of vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD). P-selectin-mediated platelet-leukocyte aggregate (PLA) formation has been shown to contribute to vaso-occlusion. Safety and pharmacology of inclacumab have previously been well characterized in over 700 subjects (healthy volunteers and patients with cardiovascular disease), at doses up to 20 mg/kg every 4 weeks for up to 9 months. The current Phase 1 study was initiated to evaluate the safety and pharmacology of inclacumab at doses of 20 mg/kg and 40 mg/kg in healthy subjects in support of a target Phase 3 dose of 30 mg/kg administered every 12 weeks to patients with SCD.Methods: Healthy adult subjects over 18 years of age without significant current or prior health conditions received a single intravenous (IV) dose of 20 mg/kg inclacumab infused over approximately one hour (Cohort 1). Following a review of safety, a second cohort received a single IV dose of 40 mg/kg infused over approximately one hour (Cohort 2). The total study duration and sample collection period was 29 weeks. Final safety and preliminary pharmacokinetics (PK), anti-drug antibody (ADA), and ex vivo thrombin receptor-activating peptide (TRAP)-activated PLA formation data are reported.Results: Fifteen subjects received a single dose of inclacumab 20 mg/kg (n=6) or 40 mg/kg (n=9). Fourteen subjects completed the study. Median age was 42 years (range 22 - 52 years); median body weight was 73.6 kg (range 63.7 - 89.3 kg). Through the pre-specified 72-hour post-infusion safety assessment period in both cohorts, no treatment-emergent adverse events (AEs) > grade 1 (mild) nor dose-limiting toxicities were reported. During the duration of the study, there were no serious AEs, infusion-related reactions, or hypersensitivity reactions. Additionally, no clinically significant changes in vital signs, laboratory findings, or ECGs were observed. The most common AEs were headache, myalgia, and contact dermatitis. The only events assessed by the investigator as potentially related to inclacumab were headache and dizziness, which were experienced by one subject (20 mg/kg) and occurred 4 hours following the end of infusion. In healthy subjects, inclacumab demonstrated dose-proportional PK over the dose range tested; PK parameter estimates were consistent with those reported for monoclonal antibodies. Geometric mean C max following single doses of 20 and 40 mg/kg were 402 and 970 µg/mL, respectively. Mean TRAP-activated predose PLA formation was 33 - 39% across cohorts and decreased to 9-14% at 2 hours following end of infusion. PLA inhibition was sustained through at least 12 weeks for both the 20 and 40 mg/kg doses. Two subjects in the 40 mg/kg cohort were ADA-positive on Week 12 and thereafter; a preliminary analysis demonstrated no apparent impact on PK or safety in these subjects.Conclusions: Inclacumab displayed a well-tolerated safety profile for up to 29 weeks following a single dose of 20 or 40 mg/kg in healthy subjects. Durable inhibition of TRAP-activated PLA formation was observed through at least 12 weeks, consistent with prior observations. Overall, the results support a Phase 3 dose of 30 mg/kg every 12 weeks in patients with SCD-related VOCs.Funding: This study was supported by Global Blood Therapeutics. DisclosuresMayer: Global Blood Therapeutics: Consultancy. Redfern: Linear Clinical Research: Current Employment; Novartis: Other: Advisory Board; Pfizer: Other: Advisory Board; Roche: Other: Advisory Board; Eisai: Other: Advisory Board; Astra Zeneca: Other: Advisory Board. Geng: Global Blood Therapeutics: Current Employment. Shi: Global Blood Therapeutics: Current Employment. van Zutphen-van Geffen: Global Blood Therapeutics: Consultancy. Kuan: Global Blood Therapeutics: Consultancy. Koeck: Global Blood Therapeutics: Consultancy. Kastrissios: Global Blood Therapeutics: Consultancy. Patel: Global Blood Therapeutics: Consultancy. Davis: Global Blood Therapeutics: Current Employment. Yue: Global Blood Therapeutics: Current Employment.

Safety of Venous Thromboembolism Prophylaxis Protocol Using a Novel Leg Exercise Apparatus in Bedridden Patients due to Spinal Diseases.

Purpose: Venous thromboembolism (VTE) is a complication in patients with a spinal disease requiring bedfast for conservative therapies. We previously developed a novel leg exercise apparatus (LEX) to encourage patients to exercise their lower extremities during bed rest. The purpose of this study was to evaluate the feasibility and safety of the LEX for the prevention of VTE in patients on bed rest due to spinal disease.Methods: Patients with spinal diseases requiring bed rest were included in the study. Exercise using the LEX was performed for ≥5 minutes. The exercises were performed three or more times per day during the bed rest period. In addition, we evaluated adverse events, such as symptomatic VTE and changes in vital signs, using venous ultrasonography, blood tests, and measurement of vital signs.Results: In total, 31 patients were enrolled (11 men, 20 women), with mean age, height, weight, and body mass index of 72.4 years, 155.2 cm, 55.0 kg, and 22.6 kg/m2, respectively. Twenty-four subjects had spinal fractures. Twenty-nine patients continued exercising until they could leave their beds. No symptomatic VTE was observed in any patient, and no other severe adverse events were observed. There were no significant changes in vital signs. The average number of exercise days with LEX and length of hospitalization were 11 and 31 days, respectively.Conclusions: This is the first study regarding mechanical thromboprophylaxis through in-bed exercise for patients with bedridden spinal disease. The LEX exercise protocol, in addition to mechanical prophylaxis with graduated compression stockings and intermittent pneumatic compression devices, for the prevention of symptomatic VTE may be feasible and safe for patients with bedridden spinal disease.

The Safety of Agalsidase Alfa Enzyme Replacement Therapy in Canadian Patients with Fabry Disease Following Implementation of a Bioreactor Process.

Background and ObjectiveFabry disease, an X-linked lysosomal storage disorder characterized by absent or reduced alpha-galactosidase activity, is a lifelong disease that impairs patients’ quality of life. Patients with Fabry disease have a considerably shortened lifespan, with mortality being mainly due to renal failure, cardiovascular disease, or cerebrovascular disease. Enzyme replacement therapy with agalsidase alfa has been shown to attenuate the renal, cardiovascular, and neuropathic disease progression associated with Fabry disease. The objective of this study was to investigate the safety of a new animal component-free version of agalsidase alfa.MethodsA phase III/IV, open-label, single-arm, multicenter safety study was conducted in Canadian patients with Fabry disease between August 2011 and September 2017 as a regulatory requirement to assess the safety of agalsidase alfa produced using an animal component-free bioreactor process. Eligible patients had a documented diagnosis of Fabry disease and satisfied current Canadian guidelines for receiving enzyme replacement therapy for Fabry disease. Following treatment with animal component-free bioreactor-processed agalsidase alfa, treatment-emergent adverse events were monitored, and post hoc analyses of infusion-related reactions by antidrug antibody and neutralizing antibody statuses were conducted. The data were analyzed using descriptive statistics.ResultsA total of 167 patients (mean [standard deviation] age, 48.9 [14.8] years), including six pediatric patients (< 18 years of age), received at least one full or partial infusion of agalsidase alfa animal component-free. Fewer than 5% of treatment-emergent adverse events (212/4446) observed in 40 patients were reported as infusion-related reactions. Antidrug antibody and neutralizing antibody status did not affect the proportion of patients with infusion-related reactions. No clinically significant changes in vital signs were observed in patients over the course of the study.ConclusionsLong-term treatment with bioreactor-produced agalsidase alfa animal component-free did not reveal new safety signals in this population of Canadian patients with Fabry disease. The treatment-emergent adverse event profile was consistent with the clinical manifestations of the disease and the known safety profile of roller bottle-produced agalsidase alfa.Clinical Trial RegistrationClinicalTrials.gov identifier NCT01298141.

Safety of Intravenous Autologous Bone Marrow-Derived Mesenchymal Cell Transplantation in 5 Patients With Reduced Left Ventricular Ejection Fraction.

Background: Although intracardiac injection or intracoronary delivery of mesenchymal stem cells (MSCs) has been reported, there have been few studies on the intravenous injection of MSCs, particularly in Japan.Methods and Results: Five patients with left ventricular ejection fraction (LVEF) ≤45% received 1.0×108 MSCs intravenously. The procedure did not induce significant changes in vital signs. One patient had an elevated body temperature after 1 day, but recovered spontaneously. Laboratory tests remained normal for 1 month after cell delivery. Computed tomography was performed after 1–2 years, and there was no evidence of malignancy.Conclusions: In this pilot study of patients with reduced LVEF, intravenous MSC delivery had no adverse effects.

Safety of PSMA-Targeted Molecular Radioligand Therapy with 177Lu-PSMA-617: Results from the Prospective Multicenter Phase 2 Trial RESIST-PC (NCT03042312).

The purpose of this analysis was to report the safety evaluation of 177Lu-PSMA-617 derived from the cohort of 64 patients exposed to 177Lu-PSMA-617 in the RESIST-PC trial NCT03042312 Methods: RESIST-PC was a prospective multicenter phase 2 trial. Patients with progressive metastatic castration-resistant prostate cancer after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, sufficient PSMA expression by PSMA PET, and no PSMA-negative soft-tissue lesions were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq per cycle) and received up to 4 cycles every 8 wk. The primary safety endpoint was assessed by collecting and grading adverse events using the Common Terminology Criteria for Adverse Events. Patients were followed until disease progression, death, serious or intolerable adverse events, study termination by sponsor, patient withdrawal, lost to follow-up, or 24 mo after the first cycle. Results: The study was closed at enrollment of 71 of 200 planned patients because of sponsorship transfer. A total of 64 (90.1%) patients received at least 1 cycle of 177Lu-PSMA-617: 28 (36%) in arm 1 (6.0 GBq) and 41 (64%) in arm 2 (7.4 GBq). There were 10 (43.5%), 19 (46.5%), and 29 (45.3%) patients who completed 4 cycles of 177Lu-PSMA-617 in the 6.0-GBq arm, 7.4-GBq arm, and overall, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade in the 6.0-GBq arm, the 7.4-GBq arm and overall, were dry mouth (47.8%; 63.4%; 57.8%, respectively), fatigue (56.5%; 51.2%; 53.1%, respectively), nausea (52.2%; 43.9%; 46.9%, respectively), and diarrhea (13.0%; 31.7%; 25.0%, respectively). Frequencies of all other TEAEs were comparable among the 2 groups (within 10% difference). Serious possibly drug-related TEAEs were reported for 5 (7.8%) patients overall (none were considered as probably or definitely related to treatment): 1 subdural hematoma grade 4, 1 anemia grade 3, 1 thrombocytopenia grade 4, 1 gastrointestinal hemorrhage grade 3, and 1 acute kidney injury grade 3. There were no clinically significant changes in vital signs in electrocardiograms in the 2 treatment groups. No trend to creatinine increase or increasing frequency of shifts from normal to abnormal over time for any hematologic parameter was noted. Conclusion:177Lu-PSMA-617 was safe and well-tolerated at 6.0 and 7.4 GBq per cycle given at 8-wk intervals with side effects easily managed with standard medical support. With established safety, further clinical trials applying individualized dosimetry and testing different 177Lu-PSMA-617 administration schemes (activity levels, time intervals) are needed to optimize tumor dose delivery and treatment efficacy.

Endoscopic-mediated, biliary hydrodynamic injection mediating clinically relevant levels of gene delivery in pig liver

Gene therapy could provide curative therapies to many inherited monogenic liver diseases. Clinical trials have largely focused on adeno-associated viruses (AAVs) for liver gene delivery. These vectors, however, are limited by small packaging size, capsid immune responses, and inability to redose. As an alternative, nonviral, hydrodynamic injection through vascular routes can successfully deliver plasmid DNA (pDNA) into mouse liver but has achieved limited success in large animal models. We explored hydrodynamic delivery of pDNA through the biliary system into the liver of pigs using ERCP and a power injector to supply hydrodynamic force. Human factor IX (hFIX), deficient in hemophilia B, was used as a model gene therapy. Biliary hydrodynamic injection was well tolerated without significant changes in vital signs, liver enzymes, hematology, or histology. No off-target pDNA delivery to other organs was detected by polymerase chain reaction. Immunohistochemistry revealed that 50.19% of the liver stained positive for hFIX after hydrodynamic injection at 5.5 mg pDNA, with every hepatic lobule in all liver lobes demonstrating hFIX expression. hFIX-positive hepatocytes were concentrated around the central vein, radiating outward across all 3 metabolic zones. Biliary hydrodynamic injection in pigs resulted in significantly higher transfection efficiency than mouse vascular hydrodynamic injection at matched pDNA per liver weight dose (32.7%-51.9% vs 18.9%, P< .0001). Biliary hydrodynamic injection using ERCP can achieve higher transfection efficiency into hepatocytes compared with AAVs at magnitudes of less cost in a clinically relevant human-sized large animal. This technology may serve as a platform for gene therapy of human liver diseases.

Efficacy and Safety of Panax Notoginseng Saponins (Xueshuantong) in Patients With Acute Ischemic Stroke (EXPECT) Trial: Rationale and Design.

Background: Although revascularization treatment is recommended as the first-line therapy for patients with non-minor acute ischemic stroke (AIS), it only benefits a minority of patients. Previous studies have reported the positive effects of Panax notoginseng saponins (PNS) (Xueshuantong lyophilized powder) on AIS, however, there have been no rigorous trials. This study aims to assess the efficacy and safety of PNS therapy for patients with AIS. Methods: The Evaluation of Xueshuantong in Patients with acutE ischemiC sTroke (EXPECT) trial is a multicenter, randomized, placebo-controlled, double-blind study aiming to enroll 480 patients in China. Eligible patients with AIS within 72 h of symptom onset will randomly receive either PNS or PNS placebo for 10 days and subsequently be followed up to 90 days. The primary outcome will be a change in the National Institute of Health Stroke Scale (NIHSS) score from baseline to 10 post-randomization days. The secondary outcomes include early neurological improvement (proportion of patients with NIHSS score 0–1), and Patient-Reported Outcomes Scale for Stroke score at 10 post-randomization days, the proportion of patients with life independence (modified Rankin Scale score of 0–1), the proportion of patients with a favorable outcome (Barthel Index ≥90), and Stroke-Specific Quality of Life score at 90 days. Adverse events or clinically significant changes in vital signs and laboratory parameters, regardless of the severity, will be recorded during the trial to assess the safety of PNS. Conclusions: To our knowledge, this study is the first double-blind trial to assess the efficacy and safety of PNS in patients with AIS. Findings of the EXPECT trial will be valuable in improving evidence regarding the clinical application of PNS therapy in patients with AIS ineligible for revascularization treatment in the reperfusion era.

GRPr Antagonist 68Ga-SB3 PET/CT Imaging of Primary Prostate Cancer in Therapy-Naïve Patients.

The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer (PCa) cells, making it an excellent tool for targeted imaging. The 68Ga-labeled GRPr antagonist SB3 has shown excellent results in preclinical and clinical studies and was selected for further clinical investigation. The aims of this phase I study were to investigate 68Ga-SB3 PET/CT imaging of primary PCa tumors and assess safety. More aims included an investigation of biodistribution and dosimetry and a comparison with pathology and GRPr expression. Methods: Ten therapy-naïve, biopsy-confirmed PCa patients planned for prostatectomy were included. A 3-h extensive PET/CT imaging protocol was performed within 2 wk before prostatectomy. Prostate tissue was evaluated for tumor localization and Gleason score, and invitro autoradiography was performed to determine GRPr expression. Available MRI scans performed within 3 mo before the study were matched. For dosimetry, residence times were estimated and effective dose to the body as well as absorbed doses to organs were calculated using the IDAC dose model, version 2.1. Results: Administration of 68Ga-SB3 (187.4 ± 40.0 MBq, 40 ± 5 μg) was well tolerated; no significant changes in vital signs or laboratory results were observed. 68Ga-SB3 PET/CT showed lesions in 8 of 10 patients. Pathologic analysis revealed a total of 16 tumor lesions, of which PET/CT showed 14, resulting in a sensitivity of 88%. 68Ga-SB3 PET/CT imaging showed uptake in 2 large prostatic intraepithelial neoplasia foci, considered a precursor to PCa, resulting in an 88% specificity. Autoradiography of tumor lesions revealed heterogeneous GRPr expression and was negative in 4 patients. Both PET/CT-negative patients had a GRPr-negative tumor. In autoradiography-positive tumors, the level of GRPr expression showed a significant correlation to tracer uptake on PET/CT. Dosimetry calculations estimated the effective dose to be 0.0144 mSv/MBq, similar to other 68Ga-labeled radiopeptides. The highest absorbed dose was detected in the physiologic GRPr-expressing pancreas (0.198 mGy/MBq), followed by the bladder wall and kidneys. Conclusion:68Ga-SB3 PET/CT is a safe imaging method and a promising tool for early PCa imaging.

Therapy of moderate cognitive impairment in the early recovery period of ischemic stroke

To assess the efficacy and safety of prospecta in the treatment of moderate cognitive impairment in the early recovery period of ischemic stroke. The study included 275 patients (mean age 64.0±8.1 years) with a history of single ischemic stroke from 3 to 6 months, with moderate cognitive impairment, and moderate activity in everyday life, who were randomized in two groups. During the screening phase, the severity of cognitive impairment was assessed with the Mini-Mental State Examination and Montreal Cognitive Assessment scales; the level of activity in everyday life was evaluated with the Barthel Scale; and quality of life was assessed with the Stroke Specific Quality of Life Scale. Patients took 2 tablets of prospecta or placebo 2 times a day for 24 weeks. The follow-up period was 4 weeks. The primary endpoint of the study was the proportion of patients with improvement in cognitive function (+1 or more on the MoCA test) after 24 weeks of treatment. The occurrence and type of adverse events (AEs), their severity, relationship to the drug, outcome, changes in vital signs, and the proportion of patients with clinically significant abnormality in laboratory tests were analyzed to assess the safety. A clinically significant improvement in cognitive function was obtained in 91.9% of patients in the prospecta group vs 82.,1% in the placebo group, (p=0.02). There were 57 AEs in 37 (27.4%) Prospecta group patients and 53 AEs in 39 (27.9%) Placebo group participants (p=1.00). No AEs were certainly associated with taking the medication. No clinically significant changes in vital signs or abnormal laboratory results were detected during the study. Prospecta is an effective and safe treatment option for patients with moderate cognitive impairment in the early recovery period of ischemic stroke.

The safety and tolerability of alkaloids from Alstonia scholaris leaves in healthy Chinese volunteers: a single-centre, randomized, double-blind, placebo-controlled phase I clinical trial

Context Capsule of alkaloids from the leaf of Alstonia scholaris (L.) R.Br. (Apocynaceae) (CALAS) is a new investigational botanical drug (No. 2011L01436) for bronchitis, post-infectious cough and asthma. Objective To observe the clinical safety and tolerability of CALAS. Materials and methods Subjects were assigned to eight cohorts, and each received randomly CALAS or placebo in one of single ascending dose (SAD) of 8, 40, 120, 240, 360, 480, or in one of multiple ascending dose (MAD) of 40 or 120 mg, three times daily for 7 days. Each cohort contained two placebo subjects. Results Sixty-two enrolled volunteers completed the study and no serious adverse events and clinically significant changes in vital signs, electrocardiography, and upper abdominal Doppler ultrasonography were observed. The ratios of treatment-emergent adverse events (TEAEs) were reported in 11/46 (23.91%) of CALAS groups and 3/16 (18.75%) of the placebo group (p > 0.05), respectively, based on the results of SAD and MAD. All TEAEs were mild, transient, and disappeared without any intervention. The TEAEs possibly related to CALAS treatment were as followings: hiccups (4/46: 8%), dry mouth and nausea (3/46: 6%), increased sleep (2/46: 4%), abdominal distension (1/46: 2%), bilirubin elevated (1/46: 2%). Discussion and conclusions CALAS is safe and well-tolerated with no unexpected or clinically relevant safety concerns up to a single dose of 360 mg and three times daily for 7 days up to 120 mg in healthy Chinese volunteers, supporting further Phase II studies.

First-in-Human Phase 1/2 Clinical Trial of SIG-001, an Innovative Shielded Cell Therapy Platform, for Hemophilia Α

First-in-Human Phase 1/2 Clinical Trial of SIG-001, an Innovative Shielded Cell Therapy Platform, for Hemophilia Α

Efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of malignant ascites

ObjectiveThe purpose of this study is to compare the difference of clinical efficacy between conventional intraperitoneal chemotherapy and HIPEC, so as to explore the clinical application value and advantages of HIPEC.DesignA retrospective analysis was conducted on 80 patients with malignant ascites admitted to our hospital from June 2017 to June 2019. The general clinical data and qualitative data of the treatment results of 80 patients with malignant ascites were processed by SPSS19.0 using χ2 test, and quantitative data were processed by t test. P < 0.05, statistical data can be considered statistically significant.ResultsThere was no significant change in vital signs and temperature in the observation group during the treatment, and the difference was not statistically significant.The short-term total effective rate of patients in the observation group was 91.11%, and the short-term total effective rate of the patients in the control group was 40%.There was no significant difference in the incidence of adverse reactions between the two groups of patients.ConclusionIntraperitoneal hyperthermic chemotherapy combined with intravenous chemotherapy can significantly control malignant ascites and has small adverse reactions, which is worthy of clinical promotion and application.

The appropriate dose of propofol for anesthesia induction in morbidly obese patients.

To investigate the optimal dose of propofol in patients with morbid obesity when the anesthetic induction dosage is calculated based on lean body weight (LBW). Forty morbid obese patients with body mass index (BMI) ≥35 kg/m2 were randomly divided into two groups: B and M. The sequential method was used in group B to study the EC50 and 95% confidence interval (CI) that met a bispectral index (BIS) value of <50 (the initial dose was set at 2.5 mg/kg). The sequential method was used in group M to obtain the EC50 and 95% CI (the initial dose was set as 3.0 mg/kg) satisfying the mean arterial pressure (MAP) fluctuation margin of >40%. The optimal dose interval of propofol was obtained by synthetically analyzing the results of the two-sequence method. There was no significant difference in the general condition between the two groups (P>0.05). There was no significant change in vital signs from when patients entered the operating room to when sufentanil was infused (P>0.05). The probit model of group B was Y=-5.411+2.343X, the EC50 of positive reaction with BIS <50 was 2.310 mg/kg, and 95% CI was 1.850-2.883 mg/kg. The probit model in the M group was Y=3.275 - 0.918X, the EC50 of positive reaction that reached >40% of the whole process of anesthetic induction was 3.567 mg/kg, and 95% CI was 1.233-7.165 mg/kg. The appropriate dosage of propofol was 2.310-3.567 mg/kg when the anesthetic induction dosage for patients with morbid obesity was calculated based on LBW. With this dose, the depth of intubation is satisfactory and the hemodynamics are stable.

Unanticipated Respiratory Compromise and Unplanned Intubations on General Medical and Surgical Floors.

Unanticipated respiratory compromise that lead to unplanned intubations is a known phenomenon in hospitalized patients. Most events occur in patients at high risk in well-monitored units; less is known about the incidence, risk factors, and trajectory of patients thought at low risk on lightly monitored general care wards. The aims of our study were to quantify demographic and clinical characteristics associated with unplanned intubations on general care floors and to analyze the medications administered, monitoring strategies, and vital-sign trajectories before the event. We performed a multicenter retrospective cohort study of hospitalized subjects on the general floor who had unanticipated, unplanned intubations on general care floors from August 2014 to February 2018. We identified 448 unplanned intubations. The incidence rate was 0.420 per 1,000 bed-days (95% CI 0.374-0.470) in the academic hospital and was 0.430 (95% CI 0.352-0.520) and 0.394 per 1,000 bed-days (95% CI 0.301-0.506) at our community hospitals. Extrapolating these rates to total hospital admissions in the United States, we estimate 64,000 events annually. The mortality rate was 49.1%. Within 12 h preceding the event, 35.3% of the subjects received opiates. All received vital-sign assessments. Most were monitored with pulse oximetry. In contrast, 2.5% were on cardiac telemetry, and only 4 subjects used capnography; 53.7% showed significant vital-sign changes in the 24 h before the event. However, 46.3% had no significant change in any vital signs. Our study showed unanticipated respiratory compromise that required an unplanned intubation of subjects on the general care floor, although not common, carried a high mortality. Besides pulse oximetry and routine vital-sign assessments, very little monitoring was in use. A significant portion of the subjects had no vital-sign abnormalities leading up to the event. Further research is needed to determine the phenotype of the different etiologies of unexpected acute respiratory failure to identify better risk stratification and monitoring strategies.

A Pilot Study Testing a Novel 3D Printed Amphibious Lower Limb Prosthesis in a Recreational Pool Setting.

IntroductionAdults with limb amputation and other physical disabilities are less likely to participate in physical activity than adults in the general population and have elevated risk of heart disease and stroke. Swimming is a physical activity often recommended for persons with limb amputation. However, a standard economical swim prosthesis that facilitates easy transition from land to water does not exist.ObjectiveThe objectives were (1) to measure ease of first‐time use and likability of a novel U.S. Food and Drug Administration (FDA)–cleared 510(k) three‐dimensional (3D) printed device, the “FIN,” in a recreational pool; and (2) to determine differences in time to complete basic swim tasks using the novel 3D printed amphibious lower limb prosthesis or a standard Swim Ankle prosthesis. Our hypotheses were the following: (1) that the novel 3D printed amphibious lower limb prosthesis would be easy and likeable upon first use; and (2) that basic swim tasks would take comparable time to complete with either device.SettingAcademic medical center and community pool in New York.ParticipantsParticipants were (N = 10) English‐speaking adults with a transtibial amputation who self‐identified to swim comfortably in a recreational setting.InterventionsParticipants completed tasks typical of recreational swimming while wearing the novel 3D printed amphibious lower limb prosthesis or a Swim Ankle.Main Outcome MeasurementsParticipants performed a series of recreational swim tasks at self‐selected speeds: entering/exiting pool, walking, swimming, and treading water, and completed a survey to assess the primary outcomes: likability, ease of use, and adverse events (feasibility).ResultsParticipants found the novel 3D printed amphibious lower limb prosthesis more likable compared to the Swim Ankle and easy to use. Time to exit the pool was significantly reduced with the novel 3D printed amphibious lower limb prosthesis, while time to complete a 25‐m lap was comparable. Participants did not show significant changes in vital signs when using either prosthesis.ConclusionsThe novel 3D printed amphibious lower limb prosthesis was likable and easy to use upon first use. This study supports conducting a larger clinical trial to determine if the data are broadly reproducible.