Two-period Crossover Trial Research Articles

Effects of a daylight intervention in the morning on circadian rhythms and sleep in geriatric patients: a randomized crossover trial.

During hospitalization, circadian rhythms and sleep are often disrupted, which has negative effects on health outcomes. Therefore, we aimed to investigate whether a daylight intervention in the morning could improve the circadian rhythms of cortisol and melatonin and enhance objective and subjective sleep quality in geriatric patients. The present study is a randomized, two-period crossover trial conducted in a geriatric ward in 15 non-demented geriatric trauma patients with a mean age of 83.1 ± 5.4years. All patients underwent a daylight intervention period, during which they were exposed to a daylight lamp from 8:00 to 13:00h, and a control period of 6days each. Cortisol and melatonin levels were measured on day 5 of each period. Objective and subjective sleep quality were assessed using actigraphy and questionnaires, respectively. Within-participant differences between periods were investigated for all parameters. A trend towards improvement in cortisol and melatonin rhythmicity was found. An increase in mean melatonin levels from 0.3 ± 0.1 to 0.9 ± 0.8ng/L was observed during the intervention period (p = .063). There was also a trend towards increased sleep efficiency, whereas subjective sleep quality tended to decrease. None of the results were significant. A daylight intervention in the morning led to a positive trend in cortisol and melatonin rhythmicity, whereas no improvement in subjective sleep quality was found. DRKS00028626 at German Clinical Trials Register, 13.06.2022.

CENTRAL BLOOD PRESSURE AND VASCULAR RESPONSES TO DIFFERENT PHYSICAL EXERCISE INTENSITIES IN NORMAL AND HIGH-NORMAL BLOOD PRESSURE AS A TOOL TO IDENTIFY EARLY VASCULAR DAMAGE

Objective: To evaluate acute changes in arterial distensibility and central pressure by high-intensity interval physical exercise (HIIPE) compared to moderate intensity continuous physical exercise (MICPE) sessions in subjects with normal and high-normal blood pressure (BP). Design and method: A randomized two-period crossover trial with 29 subjects (48±7years, 76%female, BMI=28.3±4.3kg/m2) divided into two groups according to Normal BP (120-129 and/or 80-84 mmHg) or HighNormal BP (130-139 and 85-89 mmHg) levels. They underwent either MICPE-HIIPE or HIIPE-MICPE sequences. Exercise intensity was defined according to the cardiopulmonary exercise test. The measures included aortic pulse wave velocity (PWV) and applanation tonometry (Sphygmocor®) changes at baseline, immediately, and 24 hours after each physical exercise session. Results: In HighNormal BP group, PWV was significantly lower 24h after MICPE compared to baseline (7.49 ±0.95 vs 8.20± 0.64 m/s; p=0.022). Aortic SBP was significantly lower immediately after HIIPE than baseline and 24h after MICPE (113 ± 8; 124±9 and 121±9; p < 0.05). Comparison between groups, aortic SBP was higher in HighNormal BP at baseline and immediately after MICPE compared to Normal BP (124 ±9 and 122 ±17 vs 114± 9 and 110 ±8; respectively p=0.012). Conclusions: In subjects with normal and high-normal BP, vascular distensibility response to exercise is more dependent on basal levels of stiffness and more sensitive to the stimulus of MICPE; however, changes in aortic BP are more dependent on basal BP levels and more sensitive to high-intensity stimuli.

Evaluation of Ornidazole Tablets Bioequivalence in Chinese Healthy Participants Under Fasted and Fed Conditions Using Pharmacokinetic Parameters.

Ornidazole, the third generation of nitroimidazole derivatives after metronidazole and tinidazole, it exerts both bactericidal and antiprotozoal effects. The purpose of this study was to evaluate the pharmacokinetic and bioequivalence of two ornidazole tablets manufactured by two different manufacturers based on their pharmacokinetic parameters. Fasted and fed healthy Chinese volunteers participated in a randomized sequence, single-dose, open-label, two-period crossover trial. There were 24 participants in both the fed studyand the fastedstudy. Following a 7-day washout period before receiving the alternative formulation, eligible research participants were randomly assigned (1:1) to receive a single dosage of either the reference formulation or the test formulation. Following tablet administration, plasma samples were obtained over 72 h and analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS) to evaluate ornidazole contents. maximum plasma concentration (Cmax), time to Cmax (Tmax),the area under the curve (AUC) from t = 0 to infinity (AUC0-∞), AUCfrom t = 0 to the last quantifiable concentration (AUC0-t), half-life (t1/2),and terminal elimination rate constant (z) were evaluated as pharmacokinetic (PK) parameters. The safety evaluation involved adverse events (AEs) incidence and alterations in laboratory tests (hepatic function, blood biochemistry, hematology, and urinalysis) or vital signs (temperature, pulse, and blood pressure). For the bioequivalence assessment in the fast trial, the prime PK parameters comparison between the reference and test formulation revealed that the GMR (90% CI) values for AUC0-t, Cmax, and AUC0-∞ were 100.97% (99.12-102.85%), 99.88% (90.63-110.08%), and 101.12% (99.17-103.11%), respectively. For the bioequivalence assessment in the fed trial, the key PK parameters comparison between the reference and test formulations revealed that the GMR (90% CI) values for AUC0-t, Cmax, and AUC0-∞ were 103.00% (100.94-105.11%), 101.90% (99.63-104.22%), and 102.99% (100.87-105.16%), respectively. The geometric mean ratios (GMRs) for the primary pharmacokinetic parameters (Cmax, AUC0-72, and AUC0-∞) between the two formulations and the corresponding 90% confidence intervals (CIs) were all within the range of 80.00-125.00% for both the fasting and fed states. Both treatments have comparable safety profiles. The bioequivalence and tolerability of ornidazole tablet reference and test formulations were evaluated among healthy Chinese participants under both fasting and fed conditions. The results indicated that both formulations were bioequivalent and generally well tolerated; besides, the interaction between food and drug may affect drug pharmacokinetics. CTR20212873, registered on 15 November 2021; ChiCTR2300069098, registered on 7 March 2023.

A randomised crossover trial of tezacaftor-ivacaftor for gut dysfunction in cystic fibrosis with magnetic resonance imaging (MRI) outcomes: a pilot study.

People with cystic fibrosis (CF) can experience recurrent chest infections, pancreatic exocrine insufficiency and gastrointestinal symptoms. New cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs improve lung function but gastrointestinal effects are unclear. We aimed to see if a CFTR modulator (tezacaftor-ivacaftor,TEZ/IVA) improves gastrointestinal outcomes in CF. We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ/IVA on gut physiology were measured using MRI. Participants were randomly assigned to treatment sequences AB or BA (A:TEZ/IVA, B:placebo, each 28 days), with a 28-day washout period. Participants had serial MRI scans at baseline and after 19-23 days of each treatment. Due to the COVID-19 pandemic, a protocol amendment allowed for observer-blind comparisons prior to and during TEZ/IVA. In such cases, participants were not blind to the treatment but researchers remained blind. The primary outcome was oro-caecal transit time (OCTT). Secondary outcomes included MRI metrics, symptoms and stool biomarkers. We randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ/IVA for OCTT (TEZ/IVA >360minutes [225,>360] vs. placebo 330minutes [285,>360], p=0.8) or secondary outcomes. There were no adverse events. Our data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators. NCT04006873 (02/07/2019).

Comparison of the impact of saturated fat from full-fat yogurt or low-fat yogurt and butter on cardiometabolic factors: a randomized cross-over trial.

Dairy foods are often a major contributor to dietary saturated fatty acids (SFA) intake. However, different SFA-rich foods may not have the same effects on cardiovascular risk factors. We compared full-fat yogurt with low-fat yogurt and butter for their effects on cardiometabolic risk factors in healthy individuals. Randomized, two-period crossover trial conducted from October 2022 to April 2023 among 30 healthy men and women (15 to receive full-fat yogurt first, and 15 to receive low-fat yogurt and butter first). Participants consumed a diet with 1.5-2 servings of full-fat (4%) yogurt or low-fat (< 1.5) yogurt and 10-15g of butter per day for 4 weeks, with 4 weeks wash-out when they consumed 1.5-2 servings of low-fat milk. At baseline, and the end of each 4 weeks, fasting blood samples were drawn and plasma lipids, glycemic and inflammatory markers as well as expression of some genes in the blood buffy coats fraction were determined. All 30 participants completed the two periods of the study. Apolipoprotein B was higher for the low-fat yogurt and butter [changes from baseline, + 10.06 (95%CI 4.64 to 15.47)] compared with the full-fat yogurt [-4.27 (95%CI, -11.78 to 3.23)] and the difference between two treatment periods was statistically significant (p = 0.004). Non-high-density lipoprotein increased for the low-fat yogurt and butter [change, + 5.06 (95%CI (-1.56 to 11.69) compared with the full-fat yogurt [change, - 4.90 (95%CI, -11.61 to 1.81), with no significant difference between two periods (p = 0.056). There were no between-period differences in other plasma lipid, insulin, and inflammatory biomarkers or leukocyte gene expression of ATP-binding cassette transporter 1 and CD36. This study suggests that short-term intake of SFAs from full-fat yogurt compared to intake from butter and low-fat yogurt has fewer adverse effects on plasma lipid profile. GOV: NCT05589350, 10/15/2022.

A randomised crossover trial of tezacaftor-ivacaftor for gut dysfunction in cystic fibrosis with magnetic resonance imaging (MRI) outcomes.

Background People with cystic fibrosis (CF) can experience recurrent chest infections, pancreatic exocrine insufficiency and gastrointestinal symptoms. New cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs improve lung function but gastrointestinal effects are unclear. We aimed to see if a CFTR modulator (tezacaftor-ivacaftor,TEZ/IVA) improves gastrointestinal outcomes in CF. Methods We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (2019-2020) at Nottingham University Hospitals. The effects of TEZ/IVA on gut physiology were measured using MRI. Participants were randomly assigned to treatment sequences AB or BA (A:TEZ/IVA, B:placebo, each 28 days), with a 28-day washout period. Participants had serial MRI scans at baseline and after 19-23 days of each treatment. Due to the COVID-19 pandemic, a protocol amendment allowed for observer-blind comparisons prior to and during TEZ/IVA. In such cases, participants were not blind to the treatment but researchers remained blind. The primary outcome was oro-caecal transit time (OCTT). Secondary outcomes included MRI metrics, symptoms and stool biomarkers. Results We randomised 13 participants. Before the COVID-19 pandemic 8 participants completed the full protocol and 1 dropped out. The remaining 4 participants followed the amended protocol. There were no significant differences between placebo and TEZ/IVA for OCTT (TEZ/IVA &gt;360minutes [225,&gt;360] vs. placebo 330minutes [285,&gt;360], p=0.8) or secondary outcomes. There were no adverse events. Conclusions Our data contribute to a research gap in the extra-pulmonary effects of CFTR modulators. We found no effect after TEZ/IVA on MRI metrics of gut function, GI symptoms or stool calprotectin. Effects might be detectable with larger studies, longer treatment or more effective CFTR modulators. ClinicalTrials.gov registration NCT04006873 (02/07/2019)

The specially designed nudging tableware promotes healthy food choices: Evidence from a randomized crossover trial in normal-weight young adults

PurposeTo evaluate the effects of the specially designed nudging tableware, including a plate and bowl, on individual food choices in normal-weight young adults and preliminarily explore its mechanisms. We hypothesized that the toolset could increase the choice of vegetables and decrease that of rice. MethodsA randomized, single-blind, two-period crossover trial was carried out among 40 normal-weight university students in China. All subjects completed two buffets separated by an interval of one week, wearing the eye tracker. Vegetable choice, evaluated through the proportion of vegetables, was the primary outcome, and the weight of vegetables and rice were the secondary outcomes. The mechanisms of the decision-making process were preliminarily explored through eye tracking. ResultsThe usage of the nudging tableware significantly increased the proportion of vegetables and decreased the amount of rice taken (P<0.05), while insignificantly increased the weight of vegetables (P = 0.079). Eye tracking shows that the nudging plate significantly prolonged the food-choosing process and fixation duration on vegetables (P<0.05), and the latter was positively correlated to the increased quantity of vegetables while using the nudging plate (r = 0.493, P<0.01). ConclusionThe specially designed nudging tableware might be an effective and practical tool to promote the choice of less rice and more vegetables. Mechanisms behind this change might include automatic and unconscious processes with the inconspicuously smaller capacity of the bowl and larger portion size of the vegetable segment, and increased attention triggered by the vegetable patterns and larger green underpainting.

Acute effects of a chewable beetroot-based supplement on cognitive performance: a double-blind randomized placebo-controlled crossover clinical trial

BackgroundDietary nitrate (NO3−) has been shown to be useful as an ergogenic aid with potential applications in health and disease (e.g., blood pressure control). However, there is no consensus about the effects of dietary NO3− or beetroot (BR) juice supplementation on cognitive function.ObjectiveThe aim of this study was to evaluate the effects of a single dose of a chewable BR-based supplement on cognitive performance.MethodsA double-blind randomized placebo-controlled two-period crossover clinical trial was carried out based on the extension of the CONSORT guidelines for randomized crossover trials. A total of 44 participants (24 F; 20 M; 32.7 [12.5] years; 66.3 [9.0] kg; 170 [9.2] cm; 22.8 [1.4] kg/m2) were randomly allocated to receive first either four BR-based chewable tablets (BR-CT) containing 3 g of a Beta vulgaris extract (RedNite®) or four tablets of a placebo (maltodextrin). A 4-day washout period was used before crossover. Ninety minutes after ingestion of the treatments, a neuropsychological testing battery was administered in each period. The trial was registered at clinicaltrials.gov NCT05509075.ResultsSignificant improvements with moderate effect size were found on memory consolidation at the short and long term only after BR-CT supplementation via the Rey Auditory Verbal Learning Test immediate (+ 20.69%) and delayed (+ 12.34%) recalls. Likewise, enhancement on both frontal lobe functions (+ 2.57%) and cognitive flexibility (+ 11.16%) were detected after BR-CT. There was no significant change (p < 0.05) on verbal memory of short-term digits, working memory and information processing speed. Mixed results were found on mood and anxiety through the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory (STAI-Y1 and STAI-Y2); however, sequence and period effects were seen on STAI-Y2.ConclusionsThe acute administration of a chewable BR-based supplement improves certain aspects of cognitive function in healthy females and males, particularly memory capacity and frontal skills.

Effect of melatonin in patients with low anterior resection syndrome (MELLARS): a study protocol for a randomised, placebo-controlled, crossover trial

IntroductionAfter rectal cancer surgery, a majority of patients suffer from sequelae known as low anterior resection syndrome (LARS). It is a collection of symptoms consisting of flatus and/or stool incontinence,...

Relieving psychological stress and improving sleep quality by bergamot essential oil use before bedtime and upon awakening: A randomized crossover trial

ObjectivesThe COVID-19 pandemic increased psychological stress and decreased sleep quality, especially among young people. Aromatherapy alleviates psychological stress, and bergamot essential oil helps improve depression. This study aimed to verify whether bergamot essential oil use alleviates psychological stress due to the COVID-19 pandemic and improves sleep quality and morning wakefulness. DesignA placebo-controlled, randomized, open-label, two-arm, two-period crossover trial. InterventionsEach intervention period was 1 week, with a 1-week washout period between the two periods. Participants used a bergamot or placebo spray before bedtime and upon awakening in each period. Main outcome measuresThe primary outcome measures were sleep quality and morning wakefulness, assessed using the Ogri-Shirakawa-Azumi sleep inventory MA version (OSA-MA). The secondary outcome measures were depression, anxiety, and stress, assessed using the Depression Anxiety Stress Scales-21 (DASS-21). ResultsA total of 48 university students participated in the study. A significant improvement was observed in “sleepiness on rising,” “refreshing on rising,” and “sleep length” in the bergamot group. Additionally, a significant improvement was observed in depression, anxiety, and stress. ConclusionUsing bergamot essential oil before bedtime helps relax the mind and body and provides sound sleep. It also improves mood and wakefulness when used upon awakening. Using aromatic essential oils is expected to relieve psychological stress and improve sleep quality and morning wakefulness.

A Multicomponent Cognitive Intervention May Improve Self-Reported Daily Function of Adults With Subjective Cognitive Decline.

Limited evidence exists to support cognitive intervention improving the daily function of adults with subjective cognitive decline (SCD). To examine the preliminary efficacy of a group-based multicomponent cognitive intervention that integrates Lifestyle Redesign® (LR) techniques. Single-arm two-period crossover trial; 16-wk waiting period, 16-wk intervention, and 16-wk follow-up. Memory clinic in a medical center, Taiwan. Purposive sample of adults ages >55 yr with SCD. Sixteen 1.5-hr weekly multicomponent sessions of cognitive training, cognitive rehabilitation, psychological intervention, and lifestyle intervention. Primary outcomes were (1) self-reported daily function, measured with the Activities of Daily Living Questionnaire (ADLQ) and Cognitive Failure Questionnaire; (2) performance-based daily function, measured with the Brief University of California San Diego Performance-Based Skills Assessment-Traditional Chinese Version; and (3) functional cognition, measured with the Contextual Memory Test (CMT) and Miami Prospective Memory Test. Secondary outcomes included cognitive functions, anxiety, and depression. Seventeen participants completed the intervention; 4 missed the follow-up. The generalized estimating equations model showed significant changes from baseline to pretest (control) and pretest to posttest (intervention) on the ADLQ (p = .014) and CMT-delayed (p = .003). Effects remained at the 16-wk follow-up. After adjusting for the effects of covariates, the self-reported daily function of participants ages ≤ 63 yr improved more than that of other participants (p = .003). Multicomponent cognitive interventions integrating LR techniques may improve self-reported daily function and context-dependent memory function of adults with SCD, with efficacy sustained at follow-up. What This Article Adds: A group-based multicomponent cognitive intervention consisting of cognitive training, cognitive rehabilitation, psychoeducation, and lifestyle intervention may provide benefits for the daily function and cognitive function of adults with SCD.

Hypoglycaemia frequency and physiological response after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100 in type 2 diabetes: a randomised crossover trial

Aims/hypothesisThis study compared the frequency of hypoglycaemia, time to hypoglycaemia and recovery from hypoglycaemia after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100. Furthermore, the symptomatic and counterregulatory responses to hypoglycaemia were compared between icodec and glargine U100 treatment.MethodsIn a randomised, single-centre (Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria), open-label, two-period crossover trial, individuals with type 2 diabetes (age 18–72 years, BMI 18.5–37.9 kg/m2, HbA1c ≤75 mmol/mol [≤9.0%]) treated with basal insulin with or without oral glucose-lowering drugs received once-weekly icodec (for 6 weeks) and once-daily glargine U100 (for 11 days). Total weekly doses were equimolar based on individual titration of daily glargine U100 during the run-in period (target fasting plasma glucose [PG]: 4.4–7.2 mmol/l). Randomisation was carried out by assigning a randomisation number to each participant in ascending order, which encoded to one of two treatment sequences via a randomisation list prepared prior to the start of the trial. At steady state, double and triple doses of icodec and glargine U100 were administered followed by hypoglycaemia induction: first, euglycaemia was maintained at 5.5 mmol/l by variable i.v. infusion of glucose; glucose infusion was then terminated, allowing PG to decrease to no less than 2.5 mmol/l (target PGnadir). The PGnadir was maintained for 15 min. Euglycaemia was restored by constant i.v. glucose (5.5 mg kg−1 min−1). Hypoglycaemic symptoms score (HSS), counterregulatory hormones, vital signs and cognitive function were assessed at predefined PG levels towards the PGnadir.ResultsHypoglycaemia induction was initiated in 43 and 42 participants after double dose of icodec and glargine U100, respectively, and in 38 and 40 participants after triple doses, respectively. Clinically significant hypoglycaemia, defined as PGnadir <3.0 mmol/l, occurred in comparable proportions of individuals treated with icodec vs glargine U100 after double (17 [39.5%] vs 15 [35.7%]; p=0.63) and triple (20 [52.6%] vs 28 [70.0%]; p=0.14) doses. No statistically significant treatment differences were observed in the time to decline from PG values of 5.5 mmol/l to 3.0 mmol/l (2.9–4.5 h after double dose and 2.2–2.4 h after triple dose of the insulin products). The proportion of participants with PGnadir ≤2.5 mmol/l was comparable between treatments after double dose (2 [4.7%] for icodec vs 3 [7.1%] for glargine U100; p=0.63) but higher for glargine U100 after triple dose (1 [2.6%] vs 10 [25.0%]; p=0.03). Recovery from hypoglycaemia by constant i.v. glucose infusion took <30 min for all treatments. Analyses of the physiological response to hypoglycaemia only included data from participants with PGnadir <3.0 mmol/l and/or the presence of hypoglycaemic symptoms; in total 20 (46.5%) and 19 (45.2%) individuals were included after a double dose of icodec and glargine U100, respectively, and 20 (52.6%) and 29 (72.5%) individuals were included after a triple dose of icodec and glargine U100, respectively. All counterregulatory hormones (glucagon, adrenaline [epinephrine], noradrenaline [norepinephrine], cortisol and growth hormone) increased during hypoglycaemia induction with both insulin products at both doses. Following triple doses, the hormone response was greater with icodec vs glargine U100 for adrenaline at PG3.0 mmol/l (treatment ratio 2.54 [95% CI 1.69, 3.82]; p<0.001), and cortisol at PG3.0 mmol/l (treatment ratio 1.64 [95% CI 1.13, 2.38]; p=0.01) and PGnadir (treatment ratio 1.80 [95% CI 1.09, 2.97]; p=0.02). There were no statistically significant treatment differences in the HSS, vital signs and cognitive function.Conclusions/interpretationDouble or triple doses of once-weekly icodec lead to a similar risk of hypoglycaemia compared with double or triple doses of once-daily glargine U100. During hypoglycaemia, comparable symptomatic and moderately greater endocrine responses are elicited by icodec vs glargine U100.Trial registrationClinicalTrials.gov NCT03945656.FundingThis study was funded by Novo Nordisk A/S.Graphical

Pen-administered low-dose dasiglucagon vs usual care for prevention and treatment of non-severe hypoglycaemia in people with type 1 diabetes during free-living conditions: a Phase II, randomised, open-label, two-period crossover trial

Aims/hypothesisConsumption of excess carbohydrates to manage hypoglycaemia can lead to rebound hyperglycaemia and promote weight gain. The objective of this trial was to evaluate the efficacy, safety and feasibility of pen-administered low-dose dasiglucagon for prevention and treatment of non-severe hypoglycaemia in people with type 1 diabetes during free-living conditions.MethodsTwenty-four adults with insulin pump-treated type 1 diabetes (HbA1c ≤70 mmol/mol [8.5%]) completed a randomised, open-label, two-period crossover study with 2 week periods. During the usual care and dasiglucagon intervention (DASI) periods, participants managed impending and manifested episodes of hypoglycaemia with regular carbohydrate consumption or pen-administered low-dose (80 μg) s.c. dasiglucagon, respectively. Glycaemic control was evaluated using continuous glucose monitoring (Dexcom G6) and event registration of prevention and treatment episodes.ResultsCompared with usual care, the mean difference (95% CI) in the DASI period for time in (3.9–10.0 mmol/l) and below (<3.9 mmol/l) range was 2.4 %-points (−0.7, 5.5) and −0.5 %-points (−1.2, 0.2), respectively. In the DASI period, recovery rate (time from hypoglycaemia treatment to euglycaemia) was 44% (11, 87) faster while total daily carbohydrate intake was reduced by 11% (−18, −3). Dasiglucagon use was safe and well tolerated with mild nausea being the most frequent adverse effect. Among the participants, 96% (p<0.0001) were likely to include dasiglucagon in their future routine management of hypoglycaemia.Conclusions/interpretationUse of low-dose dasiglucagon to prevent and treat non-severe hypoglycaemia during free-living conditions was safe, fast and efficacious while significantly reducing the total daily carbohydrate intake and yielding high treatment satisfaction.Trial registrationClinicalTrials.gov NCT04764968FundingThe study was an investigator-initiated trial. Zealand Pharma supplied the investigational drug and device and provided financial support for the conduct of the trial.Graphical abstract

The effects of basic body awareness therapy on balance in patients with chronic neck pain: a randomised crossover trial

Purpose This study aimed to compare the effects of basic body awareness therapy (BBAT) and conventional treatments (CT) on balance in patients with chronic neck pain. Methods Thirty-five patients with neck pain participated in this randomised two-period crossover trial. Patients were divided into A (BBAT/CT) (n = 17) and B (CT/BBAT) (n = 18) groups. Group A received BBAT twice a week for 6 weeks, whereas Group B received CT within the same parameters. After a 5-week washout period, the treatments received by the groups were changed. The primary outcome was balance, assessed via the sensory organisation test (SOT) using the computerised dynamic posturography device. The secondary outcome was pain assessed by the visual analogue scale. Assessments were performed before and after primary and secondary treatments. Results In Group A, the SOT conditions 4, 5, 6; composites score; and visual and vestibular system scores increased after BBAT; however, only condition five scores and vestibular system scores increased (p < .05) in Group B, which started with CT. Within the groups, both treatments were effective for easing pain (p < .05). Conclusions Although patients who started the therapy with BBAT showed more improvement in balance, no differences were observed between the therapies.

An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial

Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 × 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917). KalVista Pharmaceuticals.

Effect of Fludrocortisone on Intradialytic Hypotension: An Open-Label, Randomized, Crossover Study

Introduction: Intradialytic hypotension (IDH) is an important complication during chronic hemodialysis due to its adverse cardiovascular and hemodialysis outcomes. Case reports have demonstrated that administration of fludrocortisone before undergoing hemodialysis might increase intradialytic blood pressure. This study is a randomized crossover study aiming to evaluate the intradialytic hemodynamic effects of fludrocortisone. Material and Methods: A randomized, controlled two-period crossover trial was conducted at Lampang Hospital in stable chronic hemodialysis patients who experienced IDH >30% in their sessions during the past 3 months. All participants have randomly received a single dose of 0.2-mg fludrocortisone 30 min before each hemodialysis session, or had no treatment for 4 weeks. After a 2-week washout period, the participants were then switched to the other treatment for 4 weeks. The primary outcome was the mean lowest intradialytic mean arterial pressure (MAP) during the hemodialysis session. Results: A total of 17 patients were recruited with a mean age of 61.7 ± 14.8 years. By analysis of crossover design, the mean lowest intradialytic MAP was not different between receiving fludrocortisone or with no treatment (76.1 ± 12.5 vs. 73.9 ± 11.5 mm Hg, p for treatment effect = 0.331, p for period effect = 0.855, p for sequence effect = 0.870). There was no difference in the incidence of IDH between the two groups (34.4% in fludrocortisone vs. 42.7% in no treatment, p = 0.137). However, in diabetic patients and patients with residual kidney function, the incidence of IDH was significantly lower when receiving fludrocortisone (30.8 vs. 52.6%, p < 0.001, and 27.6 vs. 74.3%, p < 0.001, respectively). Conclusions: In chronic hemodialysis patients who had IDH, fludrocortisone administration did not improve intradialytic hemodynamics and did not decrease the incidence of IDH.

216-OR: Hypoglycemia Frequency and Physiological Response to Double or Triple Doses of Once-Weekly Insulin Icodec vs. Once-Daily Insulin Glargine in T2D

Insulin icodec is a basal insulin in development for once-weekly (OW) dosing. The aim of this study was to compare the hypoglycemia frequency and response after icodec vs. insulin glargine U100 (IGlar) overdosing. In a randomized, open-label, two-period crossover trial, 43 individuals with T2D on basal insulin±metformin (mean±SD age 56±9 yrs, HbA1c 7.2±0.7%) received OW icodec for 6 weeks and once-daily IGlar for 12 days at equimolar total weekly doses based on the individual daily run-in IGlar dose (mean 30±14 U) titrated to a fasting SMPG target of 80-130 mg/dL. Once at steady state, double (DD) and triple (TD) doses of icodec and IGlar were followed by hypoglycemia induction 44 h (icodec) or 7 h (IGlar) post-dose (expected time of maximum glucose-lowering effect) : First, euglycemia was maintained at 100 mg/dL by variable i.v. glucose. Then, PG was allowed to decrease to a nadir of no less than 45 mg/dL maintained for 15 min. Euglycemia was restored by constant i.v. glucose. Hypoglycemic symptom score (HSS) and counterregulatory hormones were assessed at PG 100 mg/dL and at predefined PG levels until nadir PG. For DD, clinically significant hypoglycemia (PG&amp;lt;54 mg/dL) occurred in 40 vs. 36% of subjects for icodec vs. IGlar (odds ratio 1.28; p=0.63) . For TD, clinically significant hypoglycemia occurred in 53 vs. 70% of subjects (odds ratio 0.48; p=0.14) , mean nadir PG was 56 vs. 52 mg/dL (treatment ratio 1.07; p&amp;lt;0.001) , change in HSS at nadir PG was comparable for icodec vs. IGlar (treatment difference 0.46; p=0.77) , responses in adrenaline, noradrenaline and cortisol during hypoglycemia development were greater for icodec vs. IGlar, while glucagon and growth hormone levels increased similarly. In conclusion, a DD or TD of once-weekly insulin icodec does not lead to increased risk of hypoglycemia compared to once-daily IGlar. During hypoglycemia, a comparable symptomatic response and a moderately greater endocrine response were seen for icodec vs. IGlar. Disclosure E.Svehlikova: n/a. K.Niss arfelt: Employee; Novo Nordisk. R.Cailleteau: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. S.Deller: None. K.Thomsen: Employee; Novo Nordisk. M.Hart: None. I.Mursic: None. T.Pieber: Advisory Panel; Arecor, Novo Nordisk A/S, Research Support; AstraZeneca, European Union, JDRF, Novo Nordisk Foundation, Sanofi, Speaker's Bureau; Novo Nordisk A/S, Roche Diagnostics. H.Haahr: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. Funding Novo Nordisk

Effect of intensive weekend mindfulness-based intervention on BDNF, mitochondria function, and anxiety. A randomized, crossover clinical trial

BackgroundThe previous metanalysis found that Mind-body intervention (MBI) improves neuropsychologic well-being and may increase brain-derived growth factor (BDNF). BDNF is a neurotrophic factor related to neuroplasticity. ObjectiveTo evaluate the effect of the short intensive MBI compared to control-relaxation on Site on BDNF and examine if this change is related to mitochondria function or stress-related neurohormonal activity. MethodsRandomized, controlled, two-period cross-over trial conducted in a medical center in Thailand. Healthy-meditation naive Nurse and Occupational Therapy Students, 23 assigned randomly to MBI, and 24 relaxations at the site for 8 h during the weekend. The wash-out period was three months between the two periods. All volunteers took the blood test for BDNF, mitochondrial oxidative phosphorylation (OXPHOS), Cortisol, and Heart rate variability (HRV) measurement before and Visual Analogue Scale for Anxiety (VAS-A), forward and backward digit span after each period. ResultsA total of 40 participants finished the trials. The cross over trial analysis showed a significant treatment effect between MBI and Relaxation on-site for the mean VAS-A as 9.89 (95% CI 4.81 to 19.47; P = 0.001), serum BDNF as 1.24 (95% CI 0.16 to 2.32; P = 0.04), and OXPHOS complex-1 was decreased 0.41 (95% CI 0.03–0.29 p = 0.03). There were no significant differences for digit span, cortisol, and HRV. ConclusionIn healthy meditation naïve females, even a short period of MBI may increase serum BDNF and reduce anxiety more than relaxation on-site. The more reduction of OXPHOS complex-1 in the mindfulness group suggests oxidative stress may be a more sensitive indicator than stress-related neurohormonal activity.

Effect of Food Intake on Pharmacokinetics of Oral Almonertinib: A Randomized Crossover Trial in Healthy Chinese Participants.

The third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) almonertinib (HS-10296) targets both EGFR-sensitizing and T790M resistance mutations. This randomized, open-label, two-period crossover trial investigated the effect of food intake on the single-dose pharmacokinetic properties of almonertinib and its metabolite HAS-719. Twenty healthy adults received a single dose of almonertinib tablets (110mg) on days 1 and 22 under overnight fasting or fed conditions, respectively. Plasma samples were collected 216hours post-dosing and almonertinib and HAS-719 concentrations were determined using liquid chromatography-tandem mass spectrometry. For almonertinib, the geometric mean ratio (GMR, fed/fasting) and 90% confidence interval (CI) for the area under the curve (AUC) from time 0 to 216hours and apparent oral clearance (CLz /F) were 119.9 (110.0-130.7) and 83.5 (76.6-90.9), respectively. Fasting and fed groups showed significant differences in these parameters, but not for maximum concentration (Cmax ) and time to Cmax (Tmax ). The Cmax GMR of HAS-719 was 81.7 (75.8-88.0), which decreased significantly in the fed group. The drug-related adverse reaction (AR) incidence was similar in the two groups, 50% in the fasting group and 52.6% in the fed group. ARs were mainly gastrointestinal diseases and abnormal laboratory test results, and all participants fully recovered. In conclusion, a high-fat diet slightly affected the pharmacokinetic profile of almonertinib in healthy participants, but not the safety tolerance. Therefore, almonertinib is suitable for administration under fasting or fed conditions.

207 Omega-3 and omega-6 fatty acids attenuate platelet reactivity in postmenopausal women

OBJECTIVES/GOALS: This study aimed to investigate the mechanistic effects of fish oil (âμ-3 fatty acids) or evening primrose oil (âμ-6 fatty acids) supplementation on platelet reactivity in postmenopausal women. METHODS/STUDY POPULATION: Postmenopausal women were recruited from the Ann Arbor community and the University of Michigan Medicine Center. All subjects were recruited under study protocols approved by the University of Michigan IRB between November 2015 and March 2017. We conducted a randomized, double-blind, two-period crossover trial, consisting of a 60-day supplementation period followed by a 14-day washout period in between and at the end of the study. Subjects were treated daily in random order with 2g of fish oil supplement and 2g of evening primrose oil. Blood was drawn at baseline, post-supplementation, and after washout. The effects of fatty acid supplementation on platelet aggregation, dense granule secretion and activation of basal integrin âºIIbÎ23 were assessed following supplementation and washout period. RESULTS/ANTICIPATED RESULTS: The study started with 90 postmenopausal women. A total of 78 subjects completed the study, with 12 subjects dropping out due to non-compliance and medical reasons. Supplementation with fish oil attenuated the thrombin receptor PAR4-induced platelet aggregation, whereas primrose oil supplementation attenuated aggregation mediated by PAR4 or collagen. Supplementation with âμ-3 or âμ-6 fatty acids decreased platelet dense granule secretion and attenuated basal levels of integrin âºIIbÎ23 activation. Post-washout following supplementation with primrose oil, the thrombin receptor PAR1-induced platelet aggregation was similarly attenuated. For either treatment, the observed effects post supplementation on dense granule secretion and basal integrin activation were sustained after the washout. DISCUSSION/SIGNIFICANCE: Postmenopausal women are at increased risk for a cardiovascular event due to platelet hyperactivity. This study indicates that supplementation with âμ-3 and âμ-6 fatty acids may offer significant protection for postmenopausal women against cardiovascular diseases and occlusive thrombotic events by reducing platelet reactivity.