Impact of point-of-care ultrasound use on patient referral decisions in rural Kenya: a mixed methods study.

BACKGROUND: Point-of-care ultrasound (POCUS) is recognized as a key imaging modality to bridge the diagnostic imaging gap in Low- and Middle-Income Countries (LMICs). POCUS use has been shown to impact patient management decisions including referral for specialist care. This study explored the impact of POCUS use on referral decisions among trained healthcare providers working in primary rural and peri-urban health facilities in Kenya. METHODS: A concurrent mixed methods approach was used, including a locally developed survey (N = 38) and semi-structured interviews of POCUS trained healthcare providers (N = 12). Data from the survey was descriptively analyzed and interviews were evaluated through the framework matrix method. RESULTS: Survey results of in-facility access to Xray, Ultrasonography, CT scan and MRI were 49%, 33%, 3% and 0% respectively. Only 54% of the facilities where trainees worked had the capacity to perform cesarean sections, and 38% could perform general surgery. Through a combined inductive and deductive evaluation of interview data, we found that the emerging themes could be organized through the framework of the six domains of healthcare quality as described by the Institute of Medicine: Providers reported that POCUS use allowed them to make referral decisions which were timely, safe, effective, efficient, equitable and patient-centered. Challenges included machine breakdown, poor image quality, practice isolation, lack of institutional support and insufficient feedback on the condition of patients after referral. CONCLUSION: This study highlighted that in the setting of limited imaging and surgical capacity, POCUS use by trained providers in Kenyan primary health facilities has the potential to improve the patient referral process and to promote key dimensions of healthcare quality. Therefore, there is a need to expand POCUS training programs and to develop context specific POCUS referral algorithms.

Hyaluronic Acid Spacer for Hypofractionated Prostate Radiation Therapy: A Randomized Clinical Trial.

Importance: Hypofractionated radiation therapy (RT) for prostate cancer has been associated with greater acute grade 2 gastrointestinal (GI) toxic effects compared with conventionally fractionated RT. Objective: To evaluate whether a hyaluronic acid rectal spacer could (1) improve rectal dosimetry and (2) affect acute grade 2 or higher GI toxic effects for hypofractionated RT. Design, Setting, and Participants: This randomized clinical trial was conducted from March 2020 to June 2021 among 12 centers within the US, Australia, and Spain, with a 6-month follow-up. Adult patients with biopsy-proven, T1 to T2 prostate cancer with a Gleason score 7 or less and prostate-specific antigen level of 20 ng/mL or less (to convert to µg/L, multiply by 1) were blinded to the treatment arms. Of the 260 consented patients, 201 patients (77.3%) were randomized (2:1) to the presence or absence of the spacer. Patients were stratified by intended 4-month androgen deprivation therapy use and erectile quality. Main Outcomes and Measures: For the primary outcome, we hypothesized that more than 70% of patients in the spacer group would achieve a 25% or greater reduction in the rectal volume receiving 54 Gy (V54). For the secondary outcome, we hypothesized that the spacer group would have noninferior acute (within 3 months) grade 2 or higher GI toxic effects compared with the control group, with a margin of 10%. Results: Of the 201 randomized patients, 8 (4.0%) were Asian, 26 (12.9%) Black, 42 (20.9%) Hispanic or Latino, and 153 (76.1%) White; the mean (SD) age for the spacer group was 68.6 (7.2) years and 68.4 (7.3) years for the control group. For the primary outcome, 131 of 133 (98.5%; 95% CI, 94.7%-99.8%) patients in the spacer group experienced a 25% or greater reduction in rectum V54, which was greater than the minimally acceptable 70% (P < .001). The mean (SD) reduction was 85.0% (20.9%). For the secondary outcome, 4 of 136 patients (2.9%) in the spacer group and 9 of 65 patients (13.8%) in the control group experienced acute grade 2 or higher GI toxic effects (difference, -10.9%; 95% 1-sided upper confidence limit, -3.5; P = .01). Conclusions and Relevance: The trial results suggest that rectal spacing with hyaluronic acid improved rectal dosimetry and reduced acute grade 2 or higher GI toxic effects. Rectal spacing should potentially be considered for minimizing the risk of acute grade 2 or higher toxic effects for hypofractionated RT. Trial Registration: ClinicalTrials.gov Identifier: NCT04189913.

Feasibility of project ECHO telementoring to build capacity among non-specialist emergency care providers.

The COVID-19 pandemic has led to global disruptions in emergency medicine (EM) teaching and training and highlighted the need to strengthen virtual learning platforms. This disruption coincides with essential efforts to scale up training of the emergency healthcare workforce, particularly in low-resource settings where the specialty is not well developed. Thus, there is growing interest in strengthening virtual platforms that can be used to support emergency medicine educational initiatives globally. These platforms must be robust, context specific and sustainable in low-resource environments. This report describes the implementation of Project ECHO (Extension for Community Healthcare Outcomes), a telementoring platform originally designed to extend specialist support to health care workers in rural and underserved areas in New Mexico. This platform has now been implemented successfully across the globe. We describe the challenges and benefits of the Project ECHO model to support a Point-of-Care Ultrasound (POCUS) training program for health care providers in Kenya who do not have specialty training in emergency medicine. Our experience using this platform suggests it is amenable to capacity building for non-specialist emergency care providers in low-resource settings, but key challenges to implementation exist. These include unreliable and costly internet access and lack of institutional buy-in.

Teaching emergency ultrasound to emergency medicine residents: a scoping review of structured training methods.

BACKGROUND: Over the past 2 decades, emergency ultrasound has become essential to patient care, and is a mandated competency for emergency medicine residency graduation. However, the best evidence regarding emergency ultrasound education in residency training is not known. We performed a scoping review to determine the (1) characteristics and (2) outcomes of published structured training methods, (3) the quality of publications, and (4) the implications for research and training. METHODS: We searched broadly on multiple electronic databases and screened studies from the United States and Canada describing structured emergency ultrasound training methods for emergency medicine residents. We evaluated methodological quality with the Medical Education Research Study Quality Instrument (MERSQI), and qualitatively summarized study and intervention characteristics. RESULTS: A total of 109 studies were selected from 6712 identified publications. Publications mainly reported 1 group pretest-posttest interventions (38%) conducted at a single institution (83%), training in image acquisition (82%) and interpretation (94%) domains with assessment of knowledge (44%) and skill (77%) outcomes, and training in cardiac (18%) or vascular access (15%) applications. Innovative strategies, such as gamification, cadaver models, and hand motion assessment are described. The MERSQI scores of 48 articles ranged from 0 to 15.5 (median, 11.5; interquartile range, 9.6-13.0) out of 18. Low scores reflected the absence of reported valid assessment tools (73%) and higher level outcomes (90%). CONCLUSIONS: Although innovative strategies are illustrated, the overall quality of research could be improved. The use of standardized planning and assessment tools, intentionally mapped to targeted domains and outcomes, might provide valuable formative and summative information to optimize emergency ultrasound research and training.

Evaluation of Gender Differences in Ultrasound Milestone Evaluations During Emergency Medicine Residency Training: A Multicenter Study.

OBJECTIVES: Prior literature has demonstrated incongruities among faculty evaluation of male and female residents' procedural competency during residency training. There are no known studies investigating gender differences in the assessment of procedural skills among emergency medicine (EM) residents, such as those required by ultrasound. The objective of this study was to determine if there are significant gender differences in ultrasound milestone evaluations during EM residency training. METHODS: We used a stratified, random cluster sample of Accreditation Council for Graduate Medical Education (ACGME) EM residency programs to conduct a longitudinal, retrospective cohort analysis of resident ultrasound milestone evaluation data. Milestone evaluation data were collected from a total of 16 ACGME-accredited EM residency programs representing a 4-year period. We stratified milestone data by resident gender, date of evaluation, resident postgraduate year, and cohort (residents with the same starting date). RESULTS: A total of 2,554 ultrasound milestone evaluations were collected from 1,187 EM residents (750 men [62.8%] and 444 women [37.1%]) by 104 faculty members during the study period. There was no significant overall difference in mean milestone score between female and male residents [mean difference = 0.01 (95% confidence interval {CI} = -0.04 to 0.05)]. There were no significant differences between female and male residents' mean milestone scores at the first (baseline) PGY1 evaluation (mean difference = -0.04 [95% CI = -0.09 to 0.003)] or at the final evaluation during PGY3 (mean difference = 0.02 [95% CI = -0.03 to 0.06)]. CONCLUSIONS: Despite prior studies suggesting gender bias in the evaluation of procedural competency during residency training, our study indicates that there were no significant gender-related differences in the ultrasound milestone evaluations among EM residents within training programs throughout the United States.

Assessing a novel point-of-care ultrasound training program for rural healthcare providers in Kenya.

BACKGROUND: A novel point-of-care ultrasound (PoCUS) training program was developed to train rural healthcare providers in Kenya on the Focused Assessment with Sonography for Trauma (FAST), thoracic ultrasound, basic echocardiography, and focused obstetric ultrasonography. The program includes a multimedia manual, pre-course testing, 1-day hands-on training, post-testing, 3-month post-course evaluation, and scheduled refresher training. This study evaluates the impact of the course on PoCUS knowledge and skills. Competency results were compared based on number of previous training/refresher sessions and time elapsed since prior training. METHODS: Trainees were evaluated using a computer-based, 30 question, multiple-choice test, a standardized observed structured clinical exam (OSCE), and a survey on their ultrasound use over the previous 3 months. RESULTS: Thirty-three trainees were evaluated at 21 different facilities. All trainees completed the written exam, and 32 completed the OSCE. Nine trainees out of 33 (27.3%) passed the written test. Trainees with two or more prior training sessions had statistically significant increases in their written test scores, while those with only one prior training session maintained their test scores. Time elapsed since last training was not associated with statistically significant differences in mean written test scores. Mean image quality scores (95% confidence interval) were 2.65 (2.37-2.93) for FAST, 2.41 (2.03-2.78) for thoracic, 2.22 (1.89-2.55) for cardiac, and 2.95 (2.67-3.24) for obstetric exams. There was a trend towards increased mean image quality scores with increases in the number of prior training sessions, and a trend towards decreased image quality with increased time elapsed since previous training. Forty percent of trainees reported performing more than 20 scans in the previous 3 months, while 22% reported less than 10 scans in the previous 3 months. Second and third trimester focused obstetric ultrasound was the most frequently performed scan type. Frequency of scanning was positively correlated with written test scores and image quality scores. CONCLUSION: This novel training program has the potential to improve PoCUS knowledge and skills amongst rural healthcare providers in Kenya. There is an ongoing need to increase refresher/re-training opportunities and to enhance frequency of scanning in order to improve PoCUS competency.

Telemedicine Provides Noninferior Research Informed Consent for Remote Study Enrollment: A Randomized Controlled Trial.

OBJECTIVE: Telemedicine networks are beginning to provide an avenue for conducting emergency medicine research, but using telemedicine to recruit participants for clinical trials has not been validated. The goal of this consent study was to determine whether patient comprehension of telemedicine-enabled research informed consent is noninferior to standard face-to-face (F2F) research informed consent. METHODS: A prospective, open-label randomized controlled trial was performed in a 60,000-visit Midwestern academic emergency department (ED) to test whether telemedicine-enabled research informed consent provided noninferior comprehension compared with standard consent. This study was conducted as part of a parent clinical trial evaluating the effectiveness of 0.12% oral chlorhexidine gluconate in preventing hospital-acquired pneumonia among adult ED patients with expected hospital admission. Prior to being recruited into the study, potential participants were randomized in a 1:1 allocation ratio to consent by telemedicine versus standard F2F consent. Telemedicine connectivity was provided using a commercially available interface (REACH platform, Vidyo Inc.) to an emergency physician located in another part of the ED. Comprehension of research consent (primary outcome) was measured using the modified quality of informed consent (QuIC) instrument, a validated tool for measuring research informed consent comprehension. Parent trial accrual rate and qualitative survey data were secondary outcomes. RESULTS: A total of 131 patients were randomized (n = 64, telemedicine), and 101 QuIC surveys were completed. Comprehension of research informed consent using telemedicine was not inferior to F2F consent (QuIC scores 74.4 ± 8.1 vs. 74.4 ± 6.9 on a 100-point scale, p = 0.999). Subjective understanding of consent (p = 0.194) and parent trial study accrual rates (56% vs. 69%, p = 0.142) were similar. CONCLUSION: Telemedicine is noninferior to F2F consent for delivering research informed consent, with no detected differences in comprehension and patient-reported understanding. This consent study will inform design of future telemedicine-enabled clinical trials.

Treatment of Secondary Hyperparathyroidism: Results of a Phase 2 Trial Evaluating an Intravenous Peptide Agonist of the Calcium-Sensing Receptor.

BACKGROUND/AIMS: This study evaluated the efficacy and safety of AMG416 (etelcalcitide), a novel peptide agonist of the calcium (Ca)-sensing receptor given intravenously (IV) after each hemodialysis session for the treatment of secondary hyperparathyroidism (SHPT). METHODS: Adult subjects with SHPT on hemodialysis enrolled in a 12-week, dose titration (parent) study followed by an open-label extension phase. AMG416 was administered IV, thrice weekly starting at 5 mg/session and titrated based on the subject's parathyroid hormone (PTH) and albumin-corrected Ca (cCa) to target a PTH of 150-300 pg/ml. Efficacy (percent PTH change from baseline to the efficacy analysis period during the parent study) and safety (open-label extension phase) endpoints were evaluated. RESULTS: Baseline (n = 37) mean (standard error [SE]) PTH was 853 (106 pg/ml). The mean (95% CI) percent change from baseline to the efficacy analysis period in PTH concentration was -53.6% (-60.8, -46.4). The proportion of subjects with ≥30% reduction in PTH from baseline to the efficacy assessment period (EAP) was 89% (32/36; 95% CI 73.9, 96.9). Results by the baseline PTH subgroup (≤700 vs. >700 pg/ml) were comparable for both analyses. The proportion of subjects achieving a PTH ≤300 pg/ml was 56% (n = 20/36) at the efficacy assessment period. The mean (SE) percent changes from baseline to EAP were observed for cCa -15% (1.0%) and phosphorus -10% (3.3%). Adverse events were mild to moderate in severity. The PTH reductions achieved in the parent study were maintained in the open-label extension phase. CONCLUSION: AMG416 was well tolerated and appears to be an effective agent for the treatment of SHPT in patients on hemodialysis.

Achieving regionalization through rural interhospital transfer.

Regionalization of emergency medical care aims to provide consistent and efficient high-quality care leading to optimal clinical outcomes by matching patient needs with appropriate resources at a network of hospitals. Regionalized care has been shown to improve outcomes in trauma, myocardial infarction, stroke, cardiac arrest, and acute respiratory distress syndrome. In rural areas, effective regionalization often requires interhospital transfer. The decision to transfer is complex and includes such factors as capabilities of the presenting hospital; capacity at the receiving hospital; and financial, geographic, and patient-preference considerations. Although transfer to a comprehensive center has proven benefits for some conditions, the transfer process is not without risk. These risks include clinical deterioration, limited resource availability during transport, vehicular crashes, time delays for time-sensitive care, poor communication between providers, and neglect of patient preferences. This article reviews the transfer decision, financial implications, risks, and considerations for patients undergoing rural interhospital transfer. We identify several strategies that should be considered for development of the regionalized emergency health care system of the future and identify areas where further research is necessary.

Utility of CMR Markers of Myocardial Injury in Predicting LV Functional Recovery: Results from PROTECTION AMI CMR Sub-study.

BACKGROUND: Adverse left ventricular (LV) remodelling following acute ST-segment elevation myocardial infarction (STEMI) has prognostic importance. We aimed to predict 90-day left ventricular (LV) function following acute STEMI using variables from clinical presentation, biomarkers, and cardiovascular magnetic resonance imaging (CMR). METHODS: Consecutive patients undergoing primary percutaneous coronary intervention for anterior STEMI as part of the Selective Inhibition of Delta-protein Kinase C for the Reduction of Infarct Size in Acute Myocardial Infarction (PROTECTION-AMI) trial were enrolled into the CMR sub-study at selected sites. CMR was performed at baseline (days 3 to 5) and 90 days and used to evaluate infarct size, myocardial salvage index, infarct heterogeneity, microvascular obstruction and global LV function. Biochemical markers including creatinine kinase area under the curve (CK AUC), peak CK, peak CK-myocardial band (CK-MB) and AUC, and troponin I were collected at specific time-points. RESULTS: Ninety-six patients were enrolled in the CMR sub study and 85 completed the 90-day follow-up, across 24 centres worldwide. LV ejection fraction (EF) was 56% (46-63%) at baseline and 60% (49-67%) at 90 days (p<0.001). Infarct size had moderate inverse correlation with 90-day EF (Spearman's rho=-0.7, p < 0.001) and had the strongest correlation when compared to myocardial salvage index (Spearman's rho=0.5, p=0.001), infarct heterogeneity (Spearman's rho=-0.4, p=0.02 or microvascular obstruction (Spearman's rho=-0.4, p<0.001). All biochemical markers had similar moderate relationship to LVEF at 90 days (Spearman's rho -0.6 to -0.8, p=0.001). In a multivariable model, only baseline LVEF, CMR infarct size and infarct heterogeneity independently predicted 90-day LVEF. CONCLUSION: This study reports findings of a combined CMR protocol (including myocardial oedema imaging) in a multi-centre, multi-vendor setting. We found infarct size, infarct heterogeneity and myocardial salvage index correlated favourably with 90-day LVEF, however only the former two were independently predictive.

A randomized, double-blind, phase 2 study evaluating the safety and efficacy of AMG 416 for the treatment of secondary hyperparathyroidism in hemodialysis patients.

OBJECTIVE: Secondary hyperparathyroidism (SHPT) is a frequent complication of chronic kidney disease. We evaluated AMG 416, a long-acting peptide agonist of the calcium-sensing receptor, to assess its safety, tolerability, and efficacy and to determine a safe and effective starting dose for subsequent phase 2 studies. The study was not designed to titrate AMG 416 dosing to achieve a specific PTH treatment goal. RESEARCH DESIGN AND METHODS: This is a multicenter, double-blind, randomized, placebo-controlled, dose-escalation study designed to evaluate the safety and efficacy of AMG 416 administered thrice weekly by IV bolus at the end of hemodialysis for up to 4 weeks. Eligible subjects were enrolled in one of three cohorts and treated with 5 mg of AMG 416 or placebo for 2 weeks (Cohort 1) or 5 or 10 mg of AMG 416 or placebo for 4 weeks (Cohorts 2 and 3). The primary endpoint was mean percentage change from baseline in PTH during the efficacy assessment phase (EAP) in Cohorts 2 and 3. RESULTS: Analysis of the primary endpoint showed that treatment with AMG 416 at 10 mg (Cohort 2) and 5 mg (Cohort 3) for up to 4 weeks resulted in mean 49.4% and 33.0% reductions from baseline in PTH during the efficacy assessment phase, respectively (p < 0.05 for both cohorts compared to placebo group within the cohort). A substantial proportion of subjects treated with AMG 416 achieved PTH ≤300 pg/mL and ≥30% reduction in PTH from baseline in both cohorts. The observed decreases in serum-corrected calcium were well tolerated and serum phosphate levels also tended to decrease. CONCLUSIONS: The present clinical findings support the continued development of AMG 416 as a treatment for SHPT in hemodialysis patients.

Prognostic implications of creatine kinase-MB measurements in ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention.

BACKGROUND: Peak creatine kinase (CK)-MB concentration is related to reperfusion success and clinical outcomes after fibrinolytic therapy for acute myocardial infarction. However, prognostic implications of CK-MB measurements after primary percutaneous coronary intervention (PCI), which provides more predictable and consistent reperfusion, are unknown. METHODS: We pooled 2,042 primary PCI-treated ST-segment elevation myocardial infarction (STEMI) patients from 3 trials with serial core laboratory-determined CK-MB measurements; 1,799 patients (88.1%) who survived to 36 hours and had ≥4 CK-MB measurements were studied. Cox regression modeling was performed to quantify the association between peak CK-MB concentration (and area under the time-concentration curve [AUC]) and mortality at 6 months, and death or congestive heart failure at 90 days. RESULTS: The median (25th-75th percentiles) peak CK-MB concentration and AUC measurement through 36 hours were 239 (109-429) ng/mL and 4,263 (2,081-7,124) ng/(mL h), respectively. By multivariable analysis, peak CK-MB concentration and AUC measurement were independently associated with 6-month mortality (adjusted hazard ratio [HR] 1.15, 95% CI 1.05-1.25, per 100-ng/mL increase, P = .002; and adjusted HR 1.09, 95% CI 1.03-1.14, per 1,000-ng/[mL h] increase, P < .001, respectively) and 90-day death or congestive heart failure (adjusted HR 1.26, 95% CI 1.18-1.34, P < .001; and adjusted HR 1.15, 95% CI 1.11-1.19, P < .001, respectively). CONCLUSIONS: Peak CK-MB concentration and AUC measurement are independent predictors of 3- to 6-month cardiovascular outcomes in primary PCI-treated STEMI patients. Our findings guide application of these measurements as efficacy end points in early-phase studies evaluating new therapies for STEMI.

Inhibition of delta-protein kinase C by delcasertib as an adjunct to primary percutaneous coronary intervention for acute anterior ST-segment elevation myocardial infarction: results of the PROTECTION AMI Randomized Controlled Trial.

AIMS: Delcasertib is a selective inhibitor of delta-protein kinase C (delta-PKC), which reduced infarct size during ischaemia/reperfusion in animal models and diminished myocardial necrosis and improved reperfusion in a pilot study during primary percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI). METHODS AND RESULTS: A multicentre, double-blind trial was performed in patients presenting within 6 h and undergoing primary PCI for anterior (the primary analysis cohort, n = 1010 patients) or inferior (an exploratory cohort, capped at 166 patients) STEMI. Patients with anterior STEMI were randomized to placebo or one of three doses of delcasertib (50, 150, or 450 mg/h) by intravenous infusion initiated before PCI and continued for ∼2.5 h. There were no differences between treatment groups in the primary efficacy endpoint of infarct size measured by creatine kinase MB fraction area under the curve (AUC) (median 5156, 5043, 4419, and 5253 ng h/mL in the placebo, delcasertib 50, 150, and 450 mg/mL groups, respectively) in the anterior STEMI cohort. No treatment-related differences were seen in secondary endpoints of infarct size, electrocardiographic ST-segment recovery AUC or time to stable ST recovery, or left ventricular ejection fraction at 3 months. No differences in rates of adjudicated clinical endpoints (death, heart failure, or serious ventricular arrhythmias) were observed. CONCLUSIONS: Selective inhibition of delta-PKC with intravenous infusion of delcasertib during PCI for acute STEMI in a population of patients treated according to contemporary standard of care did not reduce biomarkers of myocardial injury.

A pharmacokinetic/pharmacodynamic model for AMG 416, a novel calcimimetic peptide, following a single intravenous dose in healthy subjects.

AMG 416 is a novel peptide agonist of the calcium-sensing receptor. In support of the clinical development program, a pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to describe the relationship between plasma AMG 416 levels and serum intact parathyroid hormone (iPTH) concentrations in healthy male subjects. AMG 416 plasma concentrations were characterized by a three-compartment linear PK model, while serum iPTH levels were described by an indirect response model with drug effect on the production of iPTH characterized with an inhibitory Emax model. The production of iPTH was modeled by a circadian rhythm function. The systemic clearance of plasma AMG 416 was estimated to be 6.94 L/h. Two sine functions best described iPTH circadian rhythm with an amplitude estimated to be 0.15 and 0.08, respectively. The maximum response Emax and the potency parameter EC50 were estimated to be 0.69 and 21.0 ng/mL, respectively. This work improved our understanding of the interaction between AMG 416 PK and iPTH concentrations in healthy adult male subjects. Data suggest additional PK/PD studies with AMG 416 are warranted in the hemodialysis population.

Velcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects.

CONTEXT: Velcalcetide, also known as AMG 416, is a novel, long-acting selective peptide agonist of the calcium sensing receptor. It is being developed as an intravenous treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients with chronic kidney disease-mineral and bone disorder. OBJECTIVE: To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of velcalcetide in healthy male volunteers. METHODS: The study was a double-blind, randomized, placebo-controlled, single-dose, dose-escalation study in healthy males aged 18-45 years conducted at a single center. Each cohort included eight subjects randomized 6:2 to velcalcetide or placebo. INTERVENTION: Velcalcetide at 0.5, 2, 5 and 10 mg or placebo was administered intravenously. OUTCOMES: Measurements included plasma ionized calcium (iCa), serum total calcium, intact parathyroid hormone (iPTH), phosphorus and fibroblast growth factor-23 (FGF23), 1,25-dihydroxyvitamin D, calcitonin and urine creatinine, calcium and phosphorus and plasma pharmacokinetics for velcalcetide. Vital signs, safety biochemical and hematological indices, and adverse events were monitored throughout the study. RESULTS: Intravenous administration of velcalcetide was well tolerated with no adverse reaction of nausea, vomiting or diarrhea reported. Velcalcetide mediated dose-dependent decreases in serum iPTH at 30 min, FGF23 at 24 h and iCa at 12 h post dose (P<0.05) and in urine fractional excretion of phosphorus and increases in tubular reabsorption of phosphorus. Velcalcetide plasma exposure increased in a dose-related manner and the terminal elimination of half-life was comparable across the dose range evaluated and ranged from 18.4 to 20.0 h. CONCLUSION: Single IV doses of velcalcetide were well tolerated and associated with rapid, sustained, dose-dependent reductions in serum PTH. The results support further evaluation of velcalcetide as a treatment for SHPT in hemodialysis patients.

AMG 416 (velcalcetide) is a novel peptide for the treatment of secondary hyperparathyroidism in a single-dose study in hemodialysis patients.

AMG 416 (velcalcetide), a novel peptide agonist of the calcium-sensing receptor, lowers plasma parathyroid hormone in preclinical uremic animal models and in normal healthy individuals. Here, we studied its efficacy in hemodialysis patients suffering from secondary hyperparathyroidism. Major inclusion criteria were hemodialysis for at least 3 months, serum parathyroid hormone over 300 pg/ml, a corrected serum calcium of 9.0 mg/dl or more, and stable doses of vitamin D analogs for at least 3 weeks prior to screening. Twenty-eight patients were enrolled in one of five cohorts (5, 10, 20, 40, 60 mg). Cohorts 1-3 (four patients each) were treated in a two-period crossover design, while cohorts 4 and 5 (eight patients each) were randomized 1:1 to AMG 416 or placebo. Patients were admitted to a clinical research unit following hemodialysis and studied for 3 days prior to discharge for hemodialysis. Single intravenous doses of AMG 416 from 5 to 60 mg were well tolerated, and plasma levels increased in a dose-related manner. AMG 416 treatment was associated with significant, dose-dependent reductions in serum parathyroid hormone and fibroblast growth factor 23. Compared with placebo, all dose groups of 10 mg or more were associated with attenuation in the rise in serum phosphate during the interdialytic period. Dose-dependent reductions in serum calcium were observed and were well tolerated. Thus, AMG 416 represents a novel therapeutic approach for the treatment of secondary hyperparathyroidism in hemodialysis patients.

Pharmacology of AMG 416 (Velcalcetide), a novel peptide agonist of the calcium-sensing receptor, for the treatment of secondary hyperparathyroidism in hemodialysis patients.

A novel peptide, AMG 416 (formerly KAI-4169, and with a United States Adopted Name: velcalcetide), has been identified that acts as an agonist of the calcium-sensing receptor (CaSR). This article summarizes the in vitro and in vivo characterization of AMG 416 activity and the potential clinical utility of this novel compound. AMG 416 activates the human CaSR in vitro, acting by a mechanism distinct from that of cinacalcet, the only approved calcimimetic, since it can activate the CaSR both in the presence or the absence of physiologic levels of extracellular calcium. Administration of AMG 416 in vivo into either normal or renally compromised rats results in dose-dependent reductions in parathyroid hormone (PTH) levels and corresponding decreases in serum calcium, regardless of the baseline level of PTH. Treatment of 5/6 nephrectomized rats with AMG 416 resulted in dramatic improvements in their metabolic profile, including lower PTH and serum creatinine levels, reduced amounts of vascular calcification, attenuated parathyroid hyperplasia, and greater expression of the parathyroid gland regulators CaSR, vitamin D receptor, and FGF23 receptor compared with vehicle-treated animals. No drug accumulation was observed under this dosing regimen, and the terminal half-life of AMG 416 was estimated to be 2-4.5 hours. As a long-acting CaSR agonist, AMG 416 is an innovative new therapy for the treatment of hemodialysis patients with secondary hyperparathyroidism.

A single-center, randomized, double-blind, active, and placebo-controlled study of KAI-1678, a novel PKC-epsilon inhibitor, in the treatment of acute postoperative orthopedic pain.

OBJECTIVE: KAI-1678, a novel inhibitor of the interaction of the epsilon isoform of protein kinase C (εPKC) with its intracellular receptor, has demonstrated activity in countering hyperalgesia in several models of pain. In this controlled randomized trial, KAI-1678 was tested for analgesic activity in an orthopedic acute postoperative pain setting. DESIGN: Following hip or knee replacement surgery, subjects were treated with KAI-1678, ketorolac, or saline. Subjects recorded their pain intensity on a visual analog scale and rated their quality of analgesia. The pain intensity differences between baseline and the evaluations were summed over the first 4 hours. RESULTS: The analysis revealed that, while ketorolac displayed good analgesic activity, KAI-1678 was not significantly different than placebo. Analgesia quality ratings similarly did not show a difference between KAI-1678 and placebo in this pain model. A small excess of infusion site erythema was seen with KAI-1678, but otherwise the drug was safe and well tolerated. CONCLUSIONS: We investigated the safety and efficacy of a novel inhibitor of εPKC and provide clinical evidence that inhibition of εPKC with KAI-1678 is not effective in the treatment of acute postoperative orthopedic pain.

The safety and efficacy of KAI-1678- an inhibitor of epsilon protein kinase C (εPKC)-versus lidocaine and placebo for the treatment of postherpetic neuralgia: a crossover study design.

OBJECTIVE: Postherpetic neuralgia (PHN) occurs in approximately 10-20% of patients with herpes zoster, and the risk increases with age. In this clinical trial, we evaluated the analgesic properties of KAI-1678-an inhibitor of epsilon protein kinase C-in the treatment of neuropathic pain in patients with PHN. DESIGN: The study was a three-treatment period, double-blind, randomized, placebo and active comparator crossover trial evaluating subcutaneous infusions of KAI-1678 (25 mg), placebo, and lidocaine hydrochloride (700 mg; active comparator). PATIENTS: A total of 17 men and 6 women (N = 23) were enrolled after fulfilling diagnosis of PHN with pain persisting for ≥3 months after a segmental herpes zoster eruption. Patients had to have a mean average pain score of ≥4 points on an 11-point numerical rating scale (NRS; ranging from 0 to 10) based on at least three daily entries prior to participation in the subsequent treatment period. RESULTS: Overall, administration of KAI-1678 was generally safe and well tolerated. However, compared with placebo, KAI-1678 did not improve clinical pain scores as recorded using the NRS (0-10). In contrast, subcutaneous infusions of lidocaine were associated with a significant reduction in pain intensity at the end of the infusion. CONCLUSIONS: We conclude that KAI-1678 is not efficacious as an acute analgesic for chronic neuropathic pain because of PHN. However, for the first time, the results demonstrate that subcutaneous infusions of lidocaine are effective in treating neuropathic pain. The results of lidocaine treatment also indicate that the crossover study design was adequate to detect a clinically meaningful response in this analgesia study.