Partial Crossover Research Articles

Technology-based supportive care for metastatic breast cancer patients.

Metastatic breast cancer (MBC) patients are living longer. However, symptom burden remains a significant issue. Technology-based interventions may assist. The purpose of this study was to test a virtual assistant for addressing symptoms in MBC using the Amazon Echo Show with Alexa. In this partial crossover randomized trial, the immediate treatment group was exposed to the intervention, called Nurse AMIE (Addressing Metastatic Individuals Everyday) for 6months. The comparison group was unexposed for the first 3months and then exposed for 3months. The randomized controlled trial (RCT) during the first 3months allowed for the evaluation of intervention effects on symptoms and function. The partial crossover maximized exposure to the intervention for evaluation of feasibility, usability, and satisfaction. RCT outcome data were collected at baseline and 3months. Feasibility, usability, and satisfaction data were collected throughout the first 3months of intervention exposure. Forty-two MBC patients were randomized (1:1). Participants were 53 ± 11years old and 4 ± 7years from diagnosis with metastatic disease. No significant effects on psychosocial distress, pain, sleep disturbance, fatigue (vitality), quality of life, or chair stands were noted, despite high levels of acceptability (51%), feasibility (65%), and satisfaction (70%). A high level of participant acceptability, feasibility, usability, and satisfaction all suggest further research on this platform is warranted. The lack of statistically significant effects on symptoms, quality of life, and function may be the result of small sample size. NCT04673019 (registration date: December 17, 2020).

Pharmacokinetics, Bioequivalence, and Safety of Esomeprazole Magnesium Enteric-Coated Capsules in Healthy Chinese Subjects.

This bioequivalence study is critically important for drug production. Recently, a local pharmaceutical company produced esomeprazole magnesium enteric-coated capsules, a major drug to help to eradicate Helicobacter pylori, but the bioequivalence is not well known. The present study aimed to evaluate the bioequivalence of the 2 esomeprazole magnesium enteric-coated capsules and their pharmacokinetics and safety in 3 biological equivalence trials: fasting, feeding, and mixing. The fasting and mixing trials used single-centered randomized, open-label, single-dose, 2-treatment, 2-period, and 2-sequence crossover design, while the fed trials used single-centered, randomized, open-label, single-dose, 2-treatment, 3-period, 3-sequence partial crossover design. For the fasting and mixing trials, each of the 32 subjects was fasted overnight prior to taking the test preparations or reference preparations. In the fed trial, 54 subjects were given a high-fat meal 1 hour before the drugs were administered. Blood specimens from all subjects were collected against the light within 14hours, with the plasma drug concentration being detected by the validated ultra-performance liquid chromatography-tandem mass spectrometry analysis method. Geometric mean ratio of maximum concentration, the area under the concentration-time curve from time zero to the last measurable concentration, and area under the concentration-time curve from time zero to infinity with 90% confidence interval were calculated. The data from fasting, mixing, and fed trials met the bioequivalence criteria. No serious adverse reactions were found, suggesting that the test and reference preparations of esomeprazole magnesium enteric capsules have similar safety profile.

Metformin for chemoprevention of lung cancer in high-risk overweight or obese individuals.

TPS10636 Background: Lung cancer is the most common cause of cancer-related deaths in the United States, with tobacco smoking being the most important risk factor. However, ~60% of individuals at a high risk for lung cancer or with early-stage lung cancer are either overweight or obese. Preliminary studies suggest that the diabetes drug metformin improves survival in high BMI lung cancer patients and inhibits lung cancer progression in preclinical models, likely through its effects on the obesity-triggered changes to the immune microenvironment of the lung, particularly, the regulatory T cells (Tregs) in the airway. Given the known dysregulation of Tregs in obesity and the importance of Tregs in lung carcinogenesis, we hypothesize that metformin therapy will reprogram the immune defense of obesity in directions that are consistent with the control of nascent lung tumor development. While more generalized lung cancer prevention approaches have to date shown limited effectiveness, the targeting of a specific subset of individuals at high risk for lung cancer provides a precision prevention approach, which is likely to be more effective. Methods: This is an open-label, randomized, wait-list control trial, where 50 non-diabetic obese/overweight former smokers with over 20 pack year smoking history and PLCOm2012 Lung Cancer Risk Prediction score above 1.34% will be enrolled. They will be equally randomized to either oral metformin or no treatment for 26 weeks followed by partial crossover, whereby no-treatment subjects will receive metformin for 26 weeks. The open-label, wait-list control design allows inclusion of a control group to assess stability of the primary biomarker in an untreated population while retaining the statistical power of 40 metformin-treated subjects (assuming 20% subject attrition) and will aid accrual since all trial participants will be treated. Treatment regimen is one daily dose of metformin at 500 mg for 1 week followed by 1000 mg for the second week and 2000 mg thereafter for a total of 24 weeks. Sampling for endpoint assessment include bronchoscopy with biopsy and bronchoalveolar lavage (BAL) and blood collection before and after completion of metformin treatment. The primary endpoint is to evaluate the effect of metformin treatment on the expression of PD-1, an immune checkpoint factor, on BAL Tregs. The secondary endpoints include stability of BAL Treg PD-1 expression over time and the impact of metformin on circulating immune cells. Trial sites include Roswell Park Comprehensive Cancer Center, the Rocky Mountain Regional Veterans Affairs Medical Center, and University of British Columbia, Vancouver. Since the trial opened to accrual in March 2022, 77 patients have been pre-screened and 19 were consented. Among them, 10 participants have been enrolled and randomized, 5 in each arm. We expect to complete accrual by April 2024. Clinical trial information: NCT04931017 .

Cingulate transcranial direct current stimulation in adults with HIV.

BackgroundNeuronal dysfunction plays an important role in the high prevalence of HIV-associated neurocognitive disorders (HAND) in people with HIV (PWH). Transcranial direct current stimulation (tDCS)—with its capability to improve neuronal function—may have the potential to serve as an alternative therapeutic approach for HAND. Brain imaging and neurobehavioral studies provide converging evidence that injury to the anterior cingulate cortex (ACC) is highly prevalent and contributes to HAND in PWH, suggesting that ACC may serve as a potential neuromodulation target for HAND. Here we conducted a randomized, double-blind, placebo-controlled, partial crossover pilot study to test the safety, tolerability, and potential efficacy of anodal tDCS over cingulate cortex in adults with HIV, with a focus on the dorsal ACC (dACC).MethodsEleven PWH (47–69 years old, 2 females, 100% African Americans, disease duration 16–36 years) participated in the study, which had two phases, Phase 1 and Phase 2. During Phase 1, participants were randomized to receive ten sessions of sham (n = 4) or cingulate tDCS (n = 7) over the course of 2–3 weeks. Treatment assignments were unknown to the participants and the technicians. Neuropsychology and MRI data were collected from four additional study visits to assess treatment effects, including one baseline visit (BL, prior to treatment) and three follow-up visits (FU1, FU2, and FU3, approximately 1 week, 3 weeks, and 3 months after treatment, respectively). Treatment assignment was unblinded after FU3. Participants in the sham group repeated the study with open-label cingulate tDCS during Phase 2. Statistical analysis was limited to data from Phase 1.ResultsCompared to sham tDCS, cingulate tDCS led to a decrease in Perseverative Errors in Wisconsin Card Sorting Test (WCST), but not Non-Perseverative Errors, as well as a decrease in the ratio score of Trail Making Test—Part B (TMT-B) to TMT—Part A (TMT-A). Seed-to-voxel analysis with resting state functional MRI data revealed an increase in functional connectivity between the bilateral dACC and a cluster in the right dorsal striatum after cingulate tDCS. There were no differences in self-reported discomfort ratings between sham and cingulate tDCS.ConclusionsCingulate tDCS is safe and well-tolerated in PWH, and may have the potential to improve cognitive performance and brain function. A future study with a larger sample is warranted.

Comparative biochemical efficacy analysis of an alpha1-proteinase inhibitor (Glassia®) in patients with alpha-1 antitrypsin deficiency

Alpha1-proteinase inhibitor (A1PI) augmentation is the only specific treatment targeting the underlying deficiency in alpha1-antitrypsin deficiency (AATD). The demonstration of efficacy has been based on maintaining the biochemical surrogate endpoints of plasma antigenic and functional A1PI levels above >11 μM. Here we report a biochemical comparability analysis based on data from a phase 2/3, randomized, double-blind, two-arm study with partial crossover of Glassia® (Baxalta US Inc. Westlake Village, CA, USA) and Prolastin® (Grifols Therapeutics LLC, Research Triangle Park, NC, USA) in patients with AATD (NCT00460096). Patients (N = 50) were randomly assigned in a 2:1 ratio to receive either Glassia (n = 33) or Prolastin (n = 17), respectively. In the present study, data from patients in the per-protocol population (n = 29, Glassia; n = 12, Prolastin) were analyzed. We compared the biochemical efficacy of these two A1PI products at steady state of A1PI in plasma after weekly intravenous administration of A1PI at a dose of 60 mg/kg body weight. For both antigenic and functional A1PI levels, with or without baseline correction, the geometric mean ratios (GMRs) of plasma trough levels (Glassia/Prolastin) over a 6-week period at steady state (Weeks 7–12 post-randomization) were near or above 100%, with the 90% confidence intervals (CIs) contained within the 80%–125% interval. For antigenic A1PI, the GMR (90% CI) was 115.8% (108.1–124.2) for baseline corrected and 114.2% (109.2–119.5) for uncorrected concentrations. For functional A1PI, the GMR (90% CI) was 98.7 (92.5–105.4) for baseline corrected and 107.8% (102.3–113.5) for uncorrected concentrations. In conclusion, the biochemical efficacy of Glassia using the endpoints of plasma antigenic and functional A1PI trough concentrations at steady state was comparable with Prolastin in patients with AATD.

Response to kisspeptin and gonadotropin-releasing hormone agonist administration in Holstein-Friesian dairy heifers with positive or negative genetic merit for fertility traits

Previous research has identified that Holstein-Friesian dairy heifers with positive (POS) genetic merit for fertility traits (FertBV) reach puberty earlier than heifers with negative (NEG) FertBV. The hypothalamus-pituitary-gonadal (HPG) axis is functional in heifers before the onset of puberty, with increased LH release evident as heifers progress toward puberty. We investigated the functionality of the HPG axis in peripubertal Holstein-Friesian dairy heifers with divergent POS or NEG FertBV, hypothesizing that the earlier puberty onset of POS heifers is associated with earlier activation of the HPG axis than in NEG heifers. In experiment 1, we tested the dose responsiveness of POS heifers to an intravenous injection of either kisspeptin [Kiss; 2, 4, or 8 µg/kg of body weight (BW); n = 3 per dose] or a GnRH agonist (buserelin; 5, 10, or 20 ng/kg of BW; n = 3 per dose). The use of these 2 agonists investigates the status of the HPG axis in both the hypothalamus (Kiss) and pituitary (buserelin) glands. Doses of 4 µg/kg BW of Kiss and 10 ng/kg BW of buserelin produced submaximal LH responses and were used in experiment 2, in which previously unused POS (n = 22) and NEG (n = 18) FertBV heifers were challenged with both agonists at 10 and 12 mo of age in a partial crossover design. Heifers were randomly allocated to treatment groups, balanced for age and BW. The LH response to buserelin was greater in POS heifers than NEG heifers at 10 mo of age, with no difference in response at 12 mo. The FSH response to buserelin and the LH and FSH responses to Kiss did not differ between the POS and NEG heifers at either age. These results indicate an association between divergent genetic merit for fertility and the LH release to buserelin at 10 mo of age, supporting the hypothesis that gonadotropin responsiveness to a GnRH agonist is more advanced in POS heifers than in NEG heifers.

Co-Administration of Vonoprazan, Not Tegoprazan, Affects the Pharmacokinetics of Atorvastatin in Healthy Male Subjects.

Potassium-competitive acid blocker is a new class of drugs inhibiting gastric acid. It is controversial that vonoprazan showed the inhibitory activities of cytochrome P450 3A4. This study aimed to evaluate the pharmacokinetics (PK) of atorvastatin and safety when atorvastatin was administered alone and co-administered with vonoprazan or tegoprazan. An open-label, multiple-dose, 3-intervention, 4-sequence, 4-period, partial replicate crossover study was conducted, and three interventions were; one is orally administered atorvastatin 40 mg alone once daily for 7 days, another is atorvastatin co-administered with vonoprazan 20 mg, and the other is atorvastatin co-administered with tegoprazan 50 mg. PK blood samples were collected up to 24 h after the last dose, and PK parameters for atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were estimated by a non-compartmental method. Safety was evaluated, including adverse events and clinical laboratory tests. A total of 28 subjects completed the study. When atorvastatin was co-administered with vonoprazan, the systemic exposures of atorvastatin and atorvastatin lactone significantly increased, and the metabolic ratio of 2-hydroxyatorvastatin significantly decreased. Hypergastrinemia only occurred when atorvastatin was co-administered with vonoprazan. However, the plasma concentration profiles of atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were similar when atorvastatin was administered alone or co-administered with tegoprazan. In conclusion, after multiple doses of atorvastatin co-administered with vonoprazan in healthy subjects, the systemic exposure of atorvastatin and the incidence of hypergastrinemia increased. With tegoprazan, however, those interactions were not observed.

Post-exercise Warm or Cold Water Immersion to Augment the Cardiometabolic Benefits of Exercise Training: A Proof of Concept Trial

We investigated whether substituting the final half within 60-min bouts of exercise with passive warm or cold water immersion would provide similar or greater benefits for cardiometabolic health. Thirty healthy participants were randomized to two of three short-term training interventions in a partial crossover (12 sessions over 14–16 days, 4 week washout): (i) EXS: 60 min cycling 70% maximum heart rate (HRmax), (ii) WWI: 30 min cycling then 30 min warm water (38–40°C) immersion, and/or (iii) CWI: 30 min cycling then 30 min cold water (10–12°C) immersion. Before and after, participants completed a 20 min cycle work trial, O2max test, and an Oral Glucose Tolerance Test during which indirect calorimetry was used to measure substrate oxidation and metabolic flexibility (slope of fasting to post-prandial carbohydrate oxidation). Data from twenty two participants (25 ± 5 year, BMI 23 ± 3 kg/m2, Female = 11) were analyzed using a fixed-effects linear mixed model. O2max increased more in EXS (interaction p = 0.004) than CWI (95% CI: 1.1, 5.3 mL/kg/min, Cohen’s d = 1.35), but not WWI (CI: −0.4, 3.9 mL/kg/min, d = 0.72). Work trial distance and power increased 383 ± 223 m and 20 ± 6 W, respectively, without differences between interventions (interaction both p > 0.68). WWI lowered post-prandial glucose ∼9% (CI −1.9, −0.5 mmol/L; d = 0.63), with no difference between interventions (interaction p = 0.469). Substituting the second half of exercise with WWI provides similar cardiometabolic health benefits to time matched exercise, however, substituting with CWI does not.

First-in-human trial to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of STR-324, a dual enkephalinase inhibitor for pain management.

AimDual enkephalinase inhibitors (DENKIs) are involved in the regulation of nociception via opioid receptors. The novel compound STR‐324 belongs to the DENKI pharmacological class. This first‐in‐human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of STR‐324 in healthy male participants.MethodsThis was a randomised, double‐blind, placebo‐controlled ascending dosing study in two parts: in part 1, 30 participants received 0.004‐11.475 mg h−1 of STR‐324 or placebo (ratio 4:1) by 4 h intravenous infusion in a two‐group, partial crossover design with four treatment periods separated by 1 month wash‐out, and in part 2, 48 participants divided into three groups received either the active drug (1.25‐11.25 mg h−1) or placebo (ratio 3:1) by 48 h intravenous infusion. Safety and tolerability parameters, pharmacokinetics and pharmacodynamic effects on neurocognitive and neurophysiological tasks and on a nociceptive test battery were evaluated.ResultsNo clinically relevant changes in safety parameters were observed. All treatment‐emergent adverse events were mild and transient. The pharmacokinetics of STR‐324 could not be determined due to most concentrations being below quantifiable limits. STR‐324 metabolite concentrations were measurable, showing dose proportionality of C max and AUCinf with an estimated t 1/2 of 0.2‐0.5 h. Significant changes in pharmacodynamic parameters were observed, but these were not consistent or dose‐dependent.ConclusionSTR‐324 displayed favourable safety and tolerability profiles at all doses up to 11.475 mg h−1. Although pharmacokinetic characterisation of STR‐324 was limited, dose proportionality could be assumed based on major metabolite data assayed as proxy. No clear effects on nociceptive thresholds or other pharmacodynamic measures were observed.Trial registry: EudraCT (2014‐002402‐21) and toetsingonline.nl (63085).

Action Video Games Enhance Attentional Control and Phonological Decoding in Children with Developmental Dyslexia.

Reading acquisition is extremely difficult for about 5% of children because they are affected by a heritable neurobiological disorder called developmental dyslexia (DD). Intervention studies can be used to investigate the causal role of neurocognitive deficits in DD. Recently, it has been proposed that action video games (AVGs)—enhancing attentional control—could improve perception and working memory as well as reading skills. In a partial crossover intervention study, we investigated the effect of AVG and non-AVG training on attentional control using a conjunction visual search task in children with DD. We also measured the non-alphanumeric rapid automatized naming (RAN), phonological decoding and word reading before and after AVG and non-AVG training. After both video game training sessions no effect was found in non-alphanumeric RAN and in word reading performance. However, after only 12 h of AVG training the attentional control was improved (i.e., the set-size slopes were flatter in visual search) and phonological decoding speed was accelerated. Crucially, attentional control and phonological decoding speed were increased only in DD children whose video game score was highly efficient after the AVG training. We demonstrated that only an efficient AVG training induces a plasticity of the fronto-parietal attentional control linked to a selective phonological decoding improvement in children with DD.

Optimization of the delivery route for community group-purchasing fresh products considering customer satisfaction

For this paper, the VRP model on the total cost minimization of fixed cost, transportation cost and penalty cost is developed under the constraint of the delivery time satisfaction function for the characteristics of community group purchasing. On the genetic algorithm optimization, an elite retention mechanism is added, a partial crossover rule is used to design the crossover operator, and the examples are tested. The results show that solving the total cost function can effectively reduce the cost, and the improved genetic algorithm has good computational speed and convergence. At the same time, good satisfaction was obtained, indicating that the company cannot neglect the customer satisfaction experience while pursuing the minimum total cost, which provides a decision reference for achieving the balance between the two.

A bioequivalence study of two telmisartan 80 mg tablets in healthy Indonesian subjects: an open label, three-way, three-period, partial replicate crossover study

Telmisartan is highly variable drug indicated for treatment of hypertension. This study aimed to compare the bioavailability of two 80 mg telmisartan tablets in healthy Indonesian subjects. A randomized, open-label, single-dose, three-sequence, three-way, reference-formulation-replicated crossover study was conducted under fasting period with two-week washout period. In this study, 31 Indonesian subjects were enrolled and 28 subjects were completed the study. Serial blood samples were collected up to 72 h following drug administration. Plasma concentrations of telmisartan were determined using high-performance liquid chromatography method with fluorescence detector. The pharmacokinetic parameters of AUC0– t , AUC0–∞, and C max were assessed for bioequivalence. Bioequivalence acceptance was based on predefined criteria of 90% confidence interval (CI) of 80.00–125.00% for AUC parameters and reference-scaled-average bioequivalence of 71.73–139.42% for C max. The 90% CI for AUC0– t , AUC0–∞, and C max was 96.11–107.25%, 93.06–104.36%, and 94.23–127.01%, respectively. These results indicated that the two formulations of telmisartan were bioequivalent.

Effect of High-Intensity Interval Training on Glycemic Control in Adults With Type 1 Diabetes and Overweight or Obesity: A Randomized Controlled Trial With Partial Crossover.

OBJECTIVETo study the effect of 12 weeks of high-intensity interval training (HIIT) on glycemic control in adults with type 1 diabetes and overweight or obesity.RESEARCH DESIGN AND METHODSThirty inactive adults with type 1 diabetes who had BMI ≥25 kg/m2 and HbA1c ≥7.5% were randomized to 12 weeks of either HIIT exercise intervention consisting of 4 × 4-min HIIT (85–95% peak heart rate) performed thrice weekly or usual care control. In a partial crossover design, the control group subsequently performed the 12-week HIIT intervention. The primary end point was the change in HbA1c from baseline to 12 weeks. Glycemic and cardiometabolic outcomes were measured at 0, 12, and 24 weeks.RESULTSParticipants were aged 44 ± 10 years with diabetes duration 19 ± 11 years and BMI 30.1 ± 3.1 kg/m2. HbA1c decreased from 8.63 ± 0.66% at baseline to 8.10 ± 1.04% at 12 weeks in the HIIT intervention group (P = 0.01); however, this change was not significantly different from the control group (HIIT −0.53 ± 0.61%, control −0.14 ± 0.48%, P = 0.08). In participants who undertook at least 50% of the prescribed HIIT intervention, the HbA1c reduction was significantly greater than control (HIIT −0.64 ± 0.64% [n = 9], control −0.14 ± 0.48% [n = 15], P = 0.04). There were no differences in insulin dose, hypoglycemia on continuous glucose monitoring, blood pressure, blood lipids, body weight, or body composition between groups.CONCLUSIONSOverall, there was no significant reduction in HbA1c with a 12-week HIIT intervention in adults with type 1 diabetes. However, glycemic control may improve for people who undertake HIIT with greater adherence.

Has the Time Come to Employ Population and Individual Bioequivalence for the Evaluation of Generics?

Bioequivalence studies are a vital part of drug development. The average bioequivalence approach is the standard method of assessment to conclude whether the generic product is bioequivalent to the innovator product. Of late, debates are on whether the average bioequivalence approach adequately addresses drug interchangeability as it considers only population mean for the evaluation especially when highly variable drug products and narrow therapeutic index drugs are dealt with. Hence, the alternative approaches like population bioequivalence and individual bioequivalence assessment approaches emerge as they consider inter/intra-subject variance and subject- by-formulation variance along with population mean. The objective of the study was to apply different bioequivalence assessment approaches in a replicate bioequivalence study to evaluate the drug interchangeability. This was an open-label, single-dose, randomized, balanced, two-treatment, three-period, three-sequence, partial replicate crossover bioequivalence study of omeprazole enteric-coated tablet 20 mg conducted on 48 normal healthy subjects under fed conditions. The plasma concentration of omeprazole was analyzed by a validated bioanalytical method to determine the pharmacokinetic and statistical parameters to assess average bioequivalence, population bioequivalence, and individual bioequivalence. In this study, test formulation was shown to be bio-inequivalent to the reference formulation by average bioequivalence, population bioequivalence, and individual bioequivalence approaches. The outcome of the evaluation clearly states that the bioequivalence outcome of all these approaches are the same. Obviously, it does not mean that these three approaches provide the same outcome though the consideration of variances varies. Certainly, population bioequivalence and individual bioequivalence approach will be more accurate for the assessment of drug interchangeability.

Fe(II) spin crossover and magnetic ordering in a thiospinel studied by 57Fe and 119Sn Mössbauer spectroscopy

A previous study of the spinel CuFe0.5Ti1.5S4 revealed partial crossover of Fe(II) from a high-spin state to a low-spin state with decreasing temperature and an antiferromagnetic ordering of the residual high-spin iron below 7 K. The present study uses the possibility to introduce a small amount of 119Sn into the spinel lattice as a substitute for titanium, leading to the compound CuFe0.5Ti1.4Sn0.1S4. This compound is analysed by 119Sn Mössbauer spectroscopy in the temperature range from 4 to 510 K. The temperature dependence of the 119Sn centre shift is discussed in terms of charge transfer between Fe and Sn induced by the spin crossover. The temperature dependence of the area under the 119Sn Mössbauer absorption lines is discussed in terms of changes of the vibrational lattice properties induced by the spin crossover and the magnetic ordering. Experimental proof of a spin crossover induced by the static magnetic field below the Néel temperature is provided.

Feasibility Study of a Randomized Controlled Trial Investigating Renal Denervation as a Possible Treatment Option in Patients With Loin Pain Hematuria Syndrome.

Background:Loin Pain Hematuria Syndrome (LPHS) is a poorly understood clinical condition characterized by severe pain localized to the kidney but in the absence of identifiable urinary tract disease. There is no consensus on optimal treatment strategies for LPHS. Case reports and series have shown renal denervation via catheter-based radiofrequency ablation to be an effective therapeutic option for the treatment of LPHS. To determine whether catheter-based renal denervation is a meaningful addition to the treatment options in these often-difficult-to-treat LPHS patients, a randomized clinical trial is needed. Prior to conducting a definitive trial that focuses on patient outcomes, ensuring the feasibility of undertaking such a trial is required. As such, we will conduct a single-center randomized control feasibility trial designed to determine viability and provide framework and direction for a larger trial.Objective:The objective of the study is to determine whether conducting a randomized trial of renal denervation versus sham procedure is feasible in terms of recruitment and eligibility, and adequacy of follow-up in LPHS patients.Design:Single-center double-blinded, parallel-group, partial crossover, sham-controlled, randomized feasibility trial of 10 LPHS patients.Setting:Regina General Hospital in Regina, Saskatchewan, Canada.Patients:Ten LPHS patients who require opioid therapy.Measurements:The main feasibility outcome measures include proportion of target patients who undergo the procedure (treatment or sham) within 6 months; proportion of randomized participants (treatment or control) who entirely complete the follow-up measures at 6 weeks, 3 and 6 months; proportion of the participants who were randomized to control group, cross over after 6 months and opt-in renal denervation treatment; proportion of the crossover participants who complete the follow-up measures at 6 weeks, 3 and 6 months. Pain will be assessed using Brief Pain Inventory Score, McGill Pain Questionnaire, and a pain diary. Mood, disability, and quality of life will be measured by Center for Epidemiologic Studies Depression Scale, Oswestry Disability Index, EuroQol-5D, and Short Form Health Survey Questionnaire, respectively.Methods:Eligible participants will be randomized into either renal denervation (treatment group) or a sham treatment (control group). Data (pain, quality of life, mood, disability) will be collected from both groups at baseline, 6 weeks, 3 and 6 months after the intervention. After the initial 6-month follow-up is over, the participants who received the sham procedure will cross over into the treatment group and will be followed for an additional 6 months in the same manner as the treatment group. Descriptive statistics will be used to report outcomes for all patients.Limitations:Single-center study, small sample size.Conclusions:The lessons learnt from this trial will lay the framework and direction for conducting a multisite randomized controlled trial involving a larger cohort of patients.Trial registration:ClinicalTrials.gov (NCT04332731).

Treatment of Temporomandibular Dysfunction With Hypertonic Dextrose Injection (Prolotherapy): A Randomized Controlled Trial With Long-term Partial Crossover

ObjectiveTo assess the efficacy and longer-term effectiveness of dextrose prolotherapy injections in participants with temporomandibular dysfunction. Patients and MethodsA randomized controlled trial with masked allocation was conducted from January 14, 2013, through December 19, 2015. Forty-two participants (with 54 joints) meeting temporomandibular dysfunction criteria were randomized (1:1) to 3 monthly intra-articular injections (20% dextrose/0.2% lidocaine or 0.2% lidocaine) followed by as-needed dextrose/0.2% lidocaine injections through 1 year. Primary and secondary outcome measures included a 0 to 10 Numerical Rating Scale score for facial pain and jaw dysfunction; maximal interincisal opening (MIO) measured in millimeters, percentage of joints with 50% or more change (improvement) in pain and function, and satisfaction. ResultsRandomization produced a control group with more female participants (P=.03), longer pain duration (P=.01), and less MIO (P=.01). Upon 3-month analysis, including pertinent covariates, dextrose group participants reported decreased jaw pain (4.3±2.9 points vs 1.8±2.7 points; P=.02), jaw dysfunction (3.5±2.8 points vs 1.0±2.1 points; P=.008), and improved MIO (1.5±4.1 mm vs −1.8±5.1 mm; P=.006). Control group participants received dextrose injections beginning at 3 months. No between-group differences were noted at 12 months; pooled data suggested that jaw pain, jaw function, and MIO improved by 5.2±2.7 points (68%), 4.1±2.8 points (64%), and 2.1±5.5 mm, respectively. Pain and dysfunction improved by at least 50% in 38 of 54 (70%) and 39 of 54 (72%) jaws, respectively. ConclusionIntra-articular dextrose injection (prolotherapy) resulted in substantial improvement in jaw pain, function, and MIO compared with masked control injection at 3 months; clinical improvements endured to 12 months. Satisfaction was high. Trial Registrationclinicaltrials.gov Identifier: NCT01706172

Fixed-Dose Subcutaneous C1-Inhibitor Liquid for Prophylactic Treatment of C1-INH-HAE: SAHARA Randomized Study

Hereditary angioedema (HAE) with C1 inhibitor deficiency (C1-INH) is characterized by swelling of subcutaneous and/or submucosal tissues. To evaluate efficacy/safety of fixed-dose subcutaneous plasma-derived C1-INH (pdC1-INH) liquid for HAE attack prevention (NCT02584959). Eligible patients were ≥12 years with ≥2 monthly attacks prescreening or pre-long-term prophylaxis. In a partial crossover design, 80% of patients were randomized to placebo or pdC1-INH liquid for 14 weeks and crossed over from active to placebo or vice versa for another 14 weeks. The remainder were randomized to pdC1-INH liquid for 28 weeks. The primary efficacy endpoint was normalized number of attacks (NNA) versus placebo. Key additional endpoints were the proportion of patients achieving NNA reduction ≥50%, attack severity, number of attack-free days, and safety. Seventy-five patients were randomized and 58 (77%) completed the study. Mean age 41 years; 88% HAE type I. Least-squares means of NNA were reduced from 3.9 with placebo to 1.6 with pdC1-INH (from day 1; P < .0001). Most patients had ≥50% NNA reduction with pdC1-INH (from day 1, 78%). A total of 8.8% of placebo-treated patients were attack-free and 5.3%, 22.8%, and 63.2% had mild, moderate, and severe attacks, respectively; 37.5% of pdC1-INH-treated patients were attack-free and 8.9%, 26.8%, and 26.8% had mild, moderate, and severe attacks, respectively. Treatment-emergent adverse event rates were similar between groups (52% vs 56% for pdC1-INH crossover vs placebo, respectively). Fixed-dose subcutaneous pdC1-INH liquid was superior to placebo in preventing HAE attacks and demonstrated a favorable safety profile.

Novel Anti-CD40 Monoclonal Antibody CFZ533 in Patients with Primary Sjogren Syndrome: A Phase Iia Double-Blind, Placebo–Controlled Randomized Trial

Objectives: Primary Sjogren syndrome (pSS) is a progressive autoimmune disease characterized by formation of ectopic germinal centers in exocrine glands and secretory gland dysfunction with subset of patients developing extraglandular manifestations. CFZ533 is a novel monoclonal antibody that selectively blocks CD40, a co-stimulatory pathway receptor essential for germinal center reactions and other immune-mediated functions implicated in pSS pathogenesis. We conducted a randomized, double-blind, placebo-controlled, multicentric, partial crossover, Phase IIa Proof of Concept (PoC) study to evaluate the safety, tolerability and efficacy of CFZ533 in patients with pSS.

Addition of Metalated 3‐Alkyl‐Substituted Alkoxyallenes to Imines: Preparation of Tetrasubstituted 2,5‐Dihydropyrroles, Pyrrolidin‐3‐ones, and Pyrroles

Metalated 3‐alkyl‐substituted methoxyallenes were either generated by lithiation of the corresponding methoxyallenes or, according to a procedure of Brandsma, from 3‐alkyl‐substituted propargyl methyl ethers. Additions of these axially chiral intermediates to various imines afforded the expected allenylamines in good yields, but low diastereoselectivity. The products were cyclized either under basic conditions or with silver nitrate as catalyst to furnish the desired 1,2,3,5‐tetrasubstituted 2,5‐dihydropyrrole derivatives. Under basic conditions the cyclization is stereospecific whereas the presence of silver nitrate can induce partial crossover. The mechanisms of the two cyclization modes are discussed. Two of the N‐tosyl‐substituted dihydropyrroles were subjected to an excess of potassium tert‐butoxide giving the expected aromatized 3‐methoxypyrrole derivatives by elimination of p‐tolyl sulfinate. Acid‐promoted hydrolysis of the enol ether moiety of 2,5‐dihydropyrroles furnished the corresponding pyrrolidin‐3‐ones in good yields. The sodium borohydride reduction of these intermediates gave the corresponding 3‐hydroxypyrrolidine derivatives with high diastereoselectivity that strongly depends on the substitution pattern of the precursor. This study reveals that 3‐alkyl‐substituted methoxyallenes and their propargylic ether equivalents allow an efficient and flexible approach to 1,2,3,5‐substituted pyrrole derivatives that are useful intermediates for subsequent stereoselective elaboration and promising candidates for natural product syntheses.