Parallel-group Study Research Articles

Effectiveness of high-flow nasal cannula versus noninvasive ventilation and conventional oxygen therapy in patients weaned from invasive mechanical ventilation

BackgroundReintubation after liberation from mechanical ventilation is a common adverse event observed in the intensive care unit (ICU) with significant implications for patient outcomes. Sequential oxygen therapies, including noninvasive ventilation (NIV) and high-flow nasal cannula (HFNC) in addition to the conventional oxygen therapy (COT), are commonly employed in the post-extubation setting to lessen reintubation risk, but their comparative efficacy remains controversial.ObjectiveTo compare the efficacy of NIV, HFNC, and COT as post-extubation respiratory support.MethodsA prospective, randomized, clinical, parallel-group study enrolled extubated patients who were randomized and assigned to receive either NIV support or HFNC or COT. Primary outcomes included reintubation rates while secondary outcomes included post-extubation hemodynamics and arterial blood gases (ABGs), ICU length of stay, and ICU mortality.ResultsSixty patients were recruited and equally randomized into the three groups (20 per group). The NIV and HFNC groups had lower reintubation rates [9/20 (45%), 12/20 (60%), respectively] compared to the COT group (15/20, 75%), yet with insignificant difference between the three groups (p > 0.05). The relative risk (RR) and 95% confidence interval (CI) of reintubation were insignificantly lower in the NIV group [RR, 0.600; 95% CI 0.347–1.036, p = 0.067], and to a lesser extent in the HFNC group [RR, 0.800; 95% CI 0.516–1.240, p = 0.318] compared to the COT group, while RR between NIV and HFNC groups was 0.750; 95% CI 0.411–1.370; p = 0.350. The NIV and HFNC groups had similar, significantly shorter ICU length of stay compared to the COT group (p < 0.001). ICU mortality was lowest in the NIV group (8/20, 40%), followed by the HFNC (13/20, 65%) and highest in the COT group (15/20, 75%) with significant difference between the NIV and COT groups [RR, 0.53; 95% CI 0.29–0.96, p = 0.037].ConclusionThe study findings suggest comparable efficacy of NIV, HFNC, and COT devices in preventing reintubation within 48 h post-extubation, and NIV displayed some advantages over HFNC and COT in terms of lower reintubation and mortality rates.Trial registrationClinicalTrials.gov, NCT06593509. Registered 17 August 2024—retrospectively registered.

Designs and appropriate choices for diagnostic test accuracy study

Diagnostic tests are indispensable tools in clinical practice and are rigorously evaluated through scientifically designed accuracy studies before the clinical practice. The accuracy of these tests directly affects the correctness of the diagnosis and the rationality of treatment decisions. This article introduces the types of designs and their characteristics used in diagnostic test accuracy studies, including single-group studies, diagnostic case-control studies, single-group paired studies, and parallel-group studies. It recommends appropriate design types based on the research question stage, the diagnostic test's role in the clinical diagnostic pathway, and the actual clinical application scenario to provide suggestions for further standardizing the design of current clinical diagnostic test accuracy research. This article may help clinical researchers better understand and choose the appropriate type of diagnostic test accuracy study design to improve diagnostic test accuracy research quality.

Double-blind, placebo-controlled trial of the efficacy and safety of azelastine hydrochloride in children with perennial allergic rhinitis.

Allergic rhinitis (AR) affects up to 40% of the pediatric population. The US practice parameter recommends the use of INAH or INCS as first-line therapy for the treatment of AR. Although not directly targeted to children, the recent US Practice Parameters proposed intranasal antihistamines as first-line therapy whereas the ARIA guidelines did not. This was a randomized, double-blind, parallel-group study with a duration of 28 days. It compared Azelastine hydrochloride 0.10% and 0.15% to placebo of one spray per nostril twice daily in pediatric subjects with moderate-to-severe symptomatic perennial allergic rhinitis (PAR). A total of 486 subjects were included in the study. The change from baseline rTNSS was statistically significant for 0.15% AZE (P = .005) and 0.10% AZE (P = .015) vs. placebo. 0.15% AZE showed an LS mean change of -3.45 (20.2%) over the 28-day treatment period from a baseline value of 16.60 in rTNSS. 0.10% AZE showed an LS mean change of -3.37 (20.5%) over the 28-day treatment period from a baseline value of 16.35 in rTNSS. Somnolence was reported by one patient in the 0.1% group and one placebo patient (both of mild severity and unlikely to be related to treatment). None of the patients reported fatigue. 0.15% AZE significantly improved the overall rTNSS compared with placebo over the 28-day study period. 0.15% AZE was well tolerated in this study.

10-Week Ballroom Dance Program Improves Mood and Influences Health-Related Elements in Healthy Middle-Aged Adults.

Introduction: Sedentary lifestyles remain a persistent health issue in Japan. Ballroom dancing has recently gained attention as a potential means of maintaining physical activity, but there are very few reports on Japanese subjects. Exploratory research is therefore needed to investigate the effects of ballroom dancing on the physical and mental health of sedentary middle-aged Japanese adults. The aim of this study was to assess the impact of ballroom dancing on various health-related physical and psychological outcomes in middle-aged adults compared to a control group. Methods: A parallel-group study was carried out. Thirty healthy but inactive middle-aged adults with no previous dance experience were divided into 2 groups: an intervention group which participated in a recreational level ballroom dance program for 10 weeks (60 minutes, once per week) and a control group which had no dance lessons. Subjects completed questionnaires regarding subjective mood changes and daily physical activity. Objective measures of physical fitness, oxidative stress, antioxidant capacity, and autonomic nervous system function were also assessed before (T0) and after 10 weeks (T11) of dance practice. Results: In the subjective questionnaire, the Profile of Mood States 2 (POMS®2) survey, one of the health-related indicators, T-scores of the Total Mood Disturbance (TMD) after the intervention showed a difference (P = .014) between the dance group and the control group. In post hoc tests, increases of autonomic activity and number of days of high-intensity physical activity correlated positively with a reduction in TMD in the dance group. Conclusion: Among inactive middle-aged adults, participation in weekly ballroom dance lessons for 10 weeks improved their psychological mood compared to a control group. The improvement was found to have the positive effects of activating autonomic nervous system activity and increasing high-intensity physical activity. The results suggest that ballroom dancing may be effective in improving exercise habits and physical and mental health.

Comparative efficacy and safety of co-amoxiclav, cefpodoxime proxetil, and levofloxacin in patients with acute uncomplicated bacterial tonsillitis: A prospective, open-label, parallel group study

ABSTRACT Background: No clinical trials have compared the efficacy and safety of beta-lactam antibiotics and fluoroquinolones in acute uncomplicated bacterial tonsillitis. This study aimed to compare the efficacy and safety of co-amoxiclav (amoxicillin/clavulanic acid), cefpodoxime proxetil, and levofloxacin monotherapy in patients with acute uncomplicated bacterial tonsillitis. Methods: This was a prospective, open-label, parallel-group study where 90 patients with acute uncomplicated bacterial tonsillitis were equally divided into three groups to receive either tablet co-amoxiclav 625 mg thrice daily, tablet cefpodoxime proxetil 200 mg twice daily, or tablet levofloxacin 500 mg once daily for five days. The efficacy was assessed by subjective clinical improvement and objective bacteriological cure at the end of treatment. Safety was assessed by monitoring adverse events during the study period. Results: Co-amoxiclav, cefpodoxime proxetil, and levofloxacin showed comparable clinical responses on days three and seven; however, on day five, levofloxacin showed a significantly reduced cure rate, but a higher improvement rate, than co-amoxiclav and cefpodoxime proxetil. Bacteriologically, the responses were similar in all three groups at week 1. All drugs were well tolerated with a few self-limiting adverse effects. Conclusions: Co-amoxiclav, cefpodoxime proxetil, and levofloxacin showed a comparable clinical and bacteriological cure in acute uncomplicated bacterial tonsillitis and showed a good safety profile.

A Multicenter Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Effects of a 1-Year Regimen of Orally Inhaled Fluticasone Furoate 50 ug Once Daily on Growth Velocity in Prepubertal, Pediatric Participants With Well-Controlled Asthma

A Multicenter Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Effects of a 1-Year Regimen of Orally Inhaled Fluticasone Furoate 50 ug Once Daily on Growth Velocity in Prepubertal, Pediatric Participants With Well-Controlled Asthma

A three-arm clinical study to compare pharmacokinetic and pharmacodynamic similarity of the denosumab biosimilar LY06006 with reference denosumab in healthy male subjects

ABSTRACT Background This study aimed to evaluate the pharmacokinetic (PK), pharmacodynamic (PD) similarity, comparable safety, and immunogenicity between LY06006, European Union-sourced denosumab (EU-DEN), and United States-sourced denosumab (US-DEN). Research design and methods In this double-blind, parallel-group, and single-dose study, 300 healthy male subjects were randomized 1:1:1 to receive a 60 mg dose of either LY06006, EU-DEN, or US-DEN subcutaneously. This study lasted for 253 days. Primary PK endpoints included maximum serum concentration (Cmax), area under the concentration-time curve (AUC) from time zero to last quantifiable concentration (AUC0-t), and AUC from time zero to infinity (AUC0-inf). Pharmacokinetic equivalence was concluded if the two-sided 90% confidence interval (CI) for the geometric least squares mean ratio (GLSMR) of primary endpoints were within 80%-125%. Other PK parameters, PD parameters, safety, and immunogenicity assessments were also conducted during the study. Results The 90% CIs for ratios of GLSMR were within the predefined equivalence margin for AUC0-inf (89.0%–111.1%), AUC0-t (89.7%–111.3%), and Cmax (92.3%–106.7%). The PD parameters, safety, and immunogenicity of LY06006 were also comparable to US-DEN and EU-DEN. Conclusion LY06006 was highly similar to US-DEN and EU-DEN in terms of PK, PD, safety and immunogenicity in healthy male subjects. Clinical trial registration www.clinicaltrials.gov identifier is NCT06095427

Impact of pharmaceutical care on hospital readmissions for heart failure: a randomised trial

ObjectivesTo evaluate the impact of pharmaceutical care on the number of readmissions and visits to the emergency department due to heart failure 30 days after hospital discharge, based on a...

Rationale and Design of a Randomized, Open-Label, Parallel-Group Study of Esaxerenone Versus Angiotensin Receptor Blockers in Older Patients With Uncontrolled Hypertension on Calcium Channel Blocker Monotherapy (ESCORT-HT).

Angiotensin II receptor blockers (ARBs) and calcium channel blockers (CCBs) are commonly prescribed as first- and second-line treatments for older Japanese patients with hypertension. However, due to age-related decline in renin activity, the effectiveness of ARBs may decrease. This highlights the need for other antihypertensive agents to be used in combination with CCBs to replace ARBs for more effective blood pressure (BP) control. The ESCORT-HT study is a multicenter, randomized, controlled, open-label, parallel-group study with a 4-week run-in period and 12-week treatment period. This study aims to evaluate the efficacy of esaxerenone as a second-line treatment for hypertension and to determine whether its BP-lowering effect is noninferior to that of ARBs in older patients with uncontrolled hypertension on CCB monotherapy. The safety profiles of esaxerenone and ARBs will also be evaluated. Patients will be randomly assigned in a 1:1 ratio to receive either esaxerenone or an ARB. The primary efficacy endpoint will be the change from baseline in morning home systolic BP at the end of the treatment period. The BP-lowering effect of esaxerenone will be considered noninferior to that of ARBs if the upper limit of the two-sided 95% confidence interval (CI) for the difference in systolic BP change between esaxerenone and ARB is <3.8mmHg, and will be considered superior if the upper limit of the two-sided 95% CI is <0. The findings may elucidate the possible benefits of earlier use of mineralocorticoid receptor blockers in combination with CCBs in older patients with essential hypertension.

Clinical Pharmacokinetics and Safety of Remdesivir in Phase I Participants with Varying Degrees of Renal Impairment.

Remdesivir is a nucleotide analog prodrug approved for the treatment of COVID-19. This study evaluated the pharmacokinetics and safety of remdesivir and its metabolites (GS-704277 and GS-441524) in participants with varying degrees of renal impairment. Results of this phase I study, along with those of a phase III study, contributed to an extension of indication for remdesivir in the USA and Europe for use in patients with COVID-19 with all stages of renal impairment, including those on dialysis, with no dose adjustment. This phase I, open-label, parallel-group study enrolled participants who had mild (n=12), moderate (n = 11), or severe (n = 10) renal impairment or kidney failure (n = 6 with dialysis, n = 4 without dialysis). Healthy matched controls were enrolled as reference. Remdesivir was given as single intravenous doses of 100 mg (mild and moderate renal impairment), 40 mg (severe renal impairment, kidney failure predialysis), and 20 mg (kidney failure postdialysis and without dialysis). Plasma pharmacokinetics of remdesivir were not affected by mild, moderate, or severe renal impairment or kidney failure. Geometric least squares mean ratios ranged from 0.8 to 1.2 for remdesivir area under the plasma concentration-time curve (AUC). GS-704277 AUC was up to 2.8-fold higher and GS-441524 AUC up to 7.9-fold higher in participants with renal impairment. Adverse events and laboratory abnormalities were consistent with the existing safety profile for remdesivir. Observed pharmacokinetics for remdesivir and its metabolites in participants with renal impairment aligned with expected changes based on known routes of elimination. Remdesivir was generally safe and well tolerated in participants with renal impairment, and no new safety concerns were identified. These results, along with those from the phase III study in patients with COVID-19 with severely reduced kidney function, support the use of remdesivir in patients with any degree of renal impairment with no dose adjustments. EudraCT no. 2020-003441-10; 9 July 2020.

A randomised study and an extension study of brexpiprazole in patients with borderline personality disorder.

No drugs are currently approved for the treatment of borderline personality disorder (BPD). These studies (a randomised study and its open-label extension) aimed to evaluate the efficacy, safety and tolerability of brexpiprazole for the treatment of BPD. The Phase 2, multicentre, randomised, double-blind, placebo-controlled, parallel-group study enrolled adult outpatients with BPD. After a 1-week placebo run-in, patients were randomised 1:1 to brexpiprazole 2-3 mg/day (flexible dose) or placebo for 11 weeks. The primary endpoint was change in Zanarini Rating Scale for BPD total score from randomisation (Week 1) to Week 10 (timing of randomisation and endpoint blinded to investigators and patients). The Phase 2/3, multicentre, open-label extension study enrolled patients who completed the randomised study; all patients received brexpiprazole 2-3 mg/day (flexible dose) for 12 weeks. Safety assessments included treatment-emergent adverse events (TEAEs). Brexpiprazole was not statistically significantly different from placebo on the primary endpoint of the randomised study (N = 324 randomised; N = 110 analysed per treatment group; least squares mean difference -1.02; 95% confidence limits -2.75, 0.70; p = 0.24). Numerical efficacy advantages for brexpiprazole were observed at other time points. The most common TEAE in the randomised study was akathisia (brexpiprazole, 14.0%; placebo, 1.2%); data from the open-label study (N = 199 analysed) suggested that TEAEs were transient. The primary endpoint of the randomised study was not met. Further research on brexpiprazole in BPD is warranted based on possible efficacy signals at other time points and its safety profile.ClinicalTrials.gov identifiers: NCT04100096, NCT04186403. Funding: Otsuka, Lundbeck.

Amyloid-Related Imaging Abnormalities in Clinical Trials of Gantenerumab in Early Alzheimer Disease

Data from 2 phase 3 studies of gantenerumab, GRADUATE I/II, and their open-label extensions represent a resource to further characterize amyloid-related imaging abnormalities (ARIA), including long-term sequelae. To describe the characteristics of ARIA and risk factors and clinical consequences of ARIA-edema (ARIA-E). Secondary data collection from the GRADUATE I/II phase 3 randomized, double-blind, placebo-controlled, 116-week parallel-group studies and their open-label extensions, including PostGraduate, with up to 210 (mean, 125) weeks of total gantenerumab treatment were conducted between 2018 and 2023. The study included multicenter trials at 288 sites across 30 countries. GRADUATE I/II enrolled 985 and 980 participants, respectively, with early symptomatic Alzheimer disease (AD) and amyloid-beta (Aβ) pathology who were aged 50 to 90 years. PostGraduate enrolled 1382 participants (671 previously randomized to gantenerumab). Data were analyzed from November 2, 2022, to October 10, 2023. GRADUATE I/II participants were randomized 1:1 to gantenerumab or placebo. Nine-month uptitration was used to mitigate ARIA risk. Postbaseline safety monitoring, including brain magnetic resonance imaging (MRI) findings, and adverse events and cognitive assessments. The safety-evaluable MRI population of GRADUATE I/II comprised 1939 participants (mean age, 71.7 years; 1105 female [57.0%]). Severity of AD-related Aβ neuropathology (lower cerebrospinal fluid [CSF] Aβ42, hazard ratio [HR] for CSF Aβ42: 0.4; 95% CI, 0.2-0.7) and comorbid cerebrovascular pathology (Fazekas score: HR, 1.6; 95% CI, 1.3-2.0; total superficial siderosis count: HR, 1.9; 95% CI, 1.3-2.6; total microhemorrhage count: HR, 1.3; 95% CI, 1.0-1.5) may be important baseline risk factors for ARIA-E, in addition to apolipoprotein E (APOE) ε4 status (APOE ε4 heterozygous carrier: HR, 2.0; 95% CI, 1.4-2.8 and APOE ε4 homozygous carrier: HR, 4.7; 95% CI, 3.2-6.7). At the group level, ARIA-E did not impact long-term cognitive and functional performance (relative difference in adjusted means for Clinical Dementia Rating-Sum of Boxes was -9% in pooled GRADUATE analysis at week 116 and when censored at first ARIA-E). While taking gantenerumab, ARIA-E and ARIA-hemosiderin occurred in 24.9% (247 of 993) and 22.9% (227 of 993) participants, respectively; first ARIA-E occurred by week 64 in 86.2% (213 of 247) of participants with ARIA-E. Narratives are provided for all serious symptomatic ARIA-E cases. These results show that in addition to APOE ε4 allele count, severity of Aβ neuropathology and comorbid cerebrovascular pathology may be relevant for clinicians prescribing anti-Aβ monoclonal antibodies for early AD and developing individualized safety monitoring plans. Evaluation of these risk factors in other anti-Aβ monoclonal antibodies is recommended. ClinicalTrials.gov Identifiers: NCT03444870, NCT03443973, NCT04374253.

Dermal and Systemic Pharmacokinetics of Oral DFD-29 (minocycline hydrochloride modified release capsules, 40 mg) vs Oral Doxycycline 40 mg in Healthy Subjects

Dermal and Systemic Pharmacokinetics of Oral DFD-29 (minocycline hydrochloride modified release capsules, 40 mg) vs Oral Doxycycline 40 mg in Healthy Subjects Adelaide A. Hebert, MD,1 Srinivas Sidgiddi, MD2 1UTHealth Houston McGovern Medical School, Houston, TX; 2Journey Medical Corporation, Scottsdale, AZ Introduction: A modified-release, low-dose formulation (DFD-29) of minocycline hydrochloride (HCl) is under investigation for the treatment of rosacea. This Phase 1 study compared the dermal and systemic pharmacokinetics of DFD-29 (minocycline HCl, 40 mg) and doxycycline 40 mg in healthy, adult subjects. Methods: This randomized, open-label, single-center, parallel-group study evaluated the systemic and dermal pharmacokinetics of once-daily administration of oral DFD-29 40 mg capsules or oral doxycycline 40 mg for 21 days in healthy adult volunteers. On Day 1, subjects received the assigned study drug under fasting conditions. Blood was sampled before drug administration, every 30 minutes for 4 hours, hourly for 4 hours, and 12 and 24 hours post dose. Dermal interstitial fluid (ISF) was sampled using three open-flow microperfusion probes before dosing, hourly for 8 hours, and at 11-12, 15-16, and 23-24 hours post dose. After discharge, subjects continued to take assigned study drug once daily through Day 21, when they returned to the center and underwent the same procedures as on Day 1. Safety was evaluated by monitoring adverse events (AEs), vital signs, and laboratory tests. Results: A total of 24 subjects were randomized and completed the study. On Day 1, mean plasma Cmax levels with DFD-29 (382.8 ng/mL) and doxycycline (405.9 ng/mL) were comparable (Pr &gt; 0.716). By Day 21, mean plasma Cmax had nearly doubled with doxycycline but remained constant with DFD-29 (701.9 vs 337.7 ng/mL; Pr &gt; 0.037). Mean plasma AUC was also significantly greater with doxycycline than with DFD-29 at Day 21 (6074.8 ng.hr/mL vs 3957.6 ng.hr/mL, Pr &gt; 0.013). In contrast, mean dermal Cmax concentrations were numerically higher with DFD-29 (40 mg) than doxycycline at Day 1 (109.7 vs 81.5 ng/mL; Pr &gt; 0.117) and Day 21 (125.7 vs 114.7 ng/mL; Pr &gt; 0.681). The mean dermal AUC at Day 1 also was greater with DFD-29 than with doxycycline (1412.29 ng.hr/mL Vs 1088.55 ng.hr/mL, Pr &gt; 0.213), and at Day 21 it was similar in the two groups (1604.77 ng.hr/mL for DFD-29 and 1573.63 ng.hr/mL for doxycycline, Pr &gt; 0.954). Both DFD-29 and doxycycline 40 mg were well tolerated by the healthy volunteers. Conclusion: Minocycline from DFD-29 with its modified-release formulation provides higher dermal concentration than doxycycline from Day 1 onwards at a similar dose. The higher concentration from Day 1 at the site of action is expected to translate into a clinically meaningful impact in the treatment of patients with rosacea. This study and abstract are funded by Journey Medical Corporation.

A Phase I Clinical Trial to Evaluate the Bioequivalence of an Adalimumab Biosimilar Adalimumab-WIBP and Humira®.

The high costs associated with biological agents often limit accessibility for many patients, whereas biosimilars allow the wider application of biological treatment. The objectives of this phase I clinical trial were to compare the pharmacokinetics, immunogenicity, and safety profiles of the biosimilar adalimumab-WIBP and the reference product Humira® and to assess the precision of the bioequivalence evaluation. In this randomized, double-blind, parallel-group bioequivalence study, 164 healthy male Chinese participants were selected and randomly divided into two groups on a 1:1 ratio. The subjects were administered a single 40 mg subcutaneous dose of either adalimumab-WIBP or Humira®. Blood samples extracted at multiple intervals after administration were analyzed to interpret pharmacokinetic parameters, and any adverse events were documented. Alongside ensuring safety measures, the subjects were monitored for immunogenicity. The pharmacokinetic results demonstrated similar serum concentration-time curves in both groups. There were no significant differences in safety and no differences in immunogenicity profiles between the two groups. The bioequivalence was confirmed: the 90% confidence interval for the geometric mean ratio of the main pharmacokinetic parameters was within the range of 80-125%. The trial indicated the bioequivalence between adalimumab-WIBP and the reference product Humira® based on pharmacokinetics, immunogenicity, and safety profile. These findings reinforce the use of the adalimumab-WIBP biosimilar as a possible therapeutic alternative to Humira®.

Effects of Mediterranean Diet on Endothelial Reactivity in Individuals with High Cardiometabolic Risk: A Randomized Controlled Parallel-Group Preliminary Trial.

Endothelial dysfunction is recognized as an early modification involved in the pathogenesis of vascular diseases. Evidence suggests that the Mediterranean Diet (MD) is associated with endothelial function improvement and, in turn, plays an important role in atherosclerosis development and progression. To evaluate both acute and sustained effects of the MD on endothelial function in patients with high cardiometabolic risk. A total of 25 subjects were randomly assigned to either the MD group or the Control Diet (CD) group according to a single-blind, parallel-group study design. Endothelial function was evaluated through non-invasive flow-mediated dilation (FMD) measurements at baseline (T0) and after 8 weeks (Tw8) of the MD or CD intervention, under both 12 h fast condition (fasting) and 2 h post-meal resembling the assigned diet (2 h). Assessments were conducted by a blinded sonographer. FMD at T0-fasting was similar between MD and CD groups (6.11% ± 0.67 vs. 7.90% ± 1.65; p = 0.266). A significant difference in FMD between MD and CD groups was observed at T0-2h (12.14% ± 1.93 vs. 4.01% ± 1.03; p = 0.004), T8w-fasting (9.76% ± 1.18 vs. 5.03% ± 0.89; p = 0.008), and T8w-2h (8.99% ± 1.22 vs. 3.86% ± 0.52; p = 0.003). Oral glucose insulin sensitivity (OGIS) at T0 correlated with FMD percent changes from T0-fasting to T0-2h (r = 0.414, p = 0.044). After adjusting for age, gender, and OGIS, MD was an independent predictor of percent changes in FMD from T0-fasting to T0-2h (β: -0.582, p = 0.003), from T0-fasting to T8w-fasting (β: -0.498, p = 0.013), and from T0-fasting to T8w-2h (β: -0.479, p = 0.018). Adherence to the MD may improve endothelial function in both the short- and medium-term among patients at high cardiometabolic risk.

Beclometasone Dipropionate/Formoterol Fumarate is Similarly Effective to Budesonide/Formoterol Fumarate in Chinese Patients with COPD: The FORSYYN Double-Blind, Randomised Study

The fixed-dose combination of beclometasone dipropionate/formoterol fumarate (BDP/FF) delivered via pressurised metered-dose inhaler (pMDI) has demonstrated efficacy in chronic obstructive pulmonary disease (COPD), in studies predominantly conducted in Caucasian adults. The current study evaluated the efficacy and safety of BDP/FF pMDI in Chinese patients with COPD, as part of registration for COPD in China. This double-blind, double-dummy, randomised, parallel-group study was conducted in patients with COPD of Chinese ethnicity aged ≥40 years. After a 4-week open-label budesonide/formoterol fumarate (BUD/FF) run-in period, patients were randomised to BUD/FF or BDP/FF for 24 weeks. The primary objective was to demonstrate non-inferiority of BDP/FF to BUD/FF in terms of change from baseline in pre-dose morning forced expiratory volume in 1 sec (FEV1) at Week 24 (i.e. the lower 95% CI limit of the difference was above the pre-defined non-inferiority margin of −0.07 L). Of 750 patients randomised (377 BDP/FF; 373 BUD/FF), 87.6% completed the study. The primary endpoint was met in both the per-protocol (adjusted mean difference −0.001 L [95% CI: −0.025, 0.022], non-inferiority p < 0.001) and intention-to-treat populations (–0.001 L [–0.024, 0.022]; non-inferiority p < 0.001). There were no statistically significant BDP/FF–BUD/FF differences for the secondary endpoints, and a similar proportion of patients had adverse events (BDP/FF, 51.7%; BUD/FF, 51.2%), with most mild/moderate in severity. In conclusion, BDP/FF pMDI was non-inferior to BUD/FF in terms of pre-dose morning FEV1, supported by a range of secondary endpoints. Both treatments were similarly tolerated. The study supports the use of BDP/FF pMDI in Chinese patients with COPD. STUDY REGISTRATION China Centre for Drug Evaluation (CTR20180475).

Morphine and hydromorphone pharmacokinetics in human volunteers: population-based modelling of interindividual and opioid-related variability

BackgroundMorphine and hydromorphone have differing onsets, magnitudes, and durations of effects and side-effects. Differences between opioids in their interindividual variabilities in pharmacokinetics and pharmacodynamics might influence rational drug selection. Crossover drug studies can provide more informative interindividual variability data than parallel group studies. Using data from a crossover study of i.v. morphine and hydromorphone in healthy volunteers, we tested the hypothesis that morphine and hydromorphone differ in their interindividual pharmacokinetic variability. MethodsArterial opioid and metabolite concentrations from a randomised crossover study in 51 volunteers receiving a 2-h infusion of hydromorphone (0.05 or 0.1 mg kg−1 i.v.) or morphine (total 0.1 or 0.2 mg kg−1 i.v.) 1–2 weeks apart were evaluated with a three-compartmental model for parent opioid and incorporating glucuronides using population modelling (NONMEM). The primary outcome was interindividual variability in pharmacokinetics, based on the coefficient of variation (%CV) of individual model parameters, calculated as √[exp(ω2)–1]×100 where ω2 is the interindividual variability. ResultsData were analysed per drug and in a combined morphine–hydromorphone model. Both analyses indicate that interindividual variabilities for hydromorphone and morphine were comparable with %CV ranging from 9% to 31% for structural model parameters (combined analysis). Similarly, additive and relative residual errors had comparable variabilities, 20–40% and 72–87%, respectively, for morphine and hydromorphone (combined analysis). ConclusionsMorphine and hydromorphone did not differ in a statistically significant or clinically meaningful manner in their interindividual pharmacokinetic variability. Interindividual pharmacokinetic variability does not appear a meaningful consideration in the choice between these two opioids.

Safety, pharmacokinetics, and early bactericidal activity of quabodepistat in combination with delamanid, bedaquiline, or both in adults with pulmonary tuberculosis: a randomised, active-controlled, open-label trial

Quabodepistat (formerly OPC-167832) showed potent activity in preclinical studies and in the first stage of an early bactericidal activity study in adults with smear-positive, drug-susceptible pulmonary tuberculosis. Stage 2 of this study was designed to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of quabodepistat in combination with delamanid, bedaquiline, or both versus rifampicin, isoniazid, ethambutol, and pyrazinamide combination therapy for 14 days. Stage 2 of this open-label, active-controlled, randomised, parallel-group study was conducted at two research sites in South Africa in adults (aged 18-64 years) with drug-susceptible pulmonary tuberculosis. Eligible participants had a BMI of 16-32 kg/m2 and the ability to produce an adequate volume of sputum (≥10 mL overnight) and were excluded if they had drug-resistant tuberculosis or previous treatment for Mycobacterium tuberculosis within the past 3 years. Participants were centrally randomly assigned via interactive web response technology system, with no stratification, into four treatment groups in a ratio of 14:14:14:4 (quabodepistat 30 mg plus delamanid 300 mg, quabodepistat 30 mg plus bedaquiline 400 mg, or quabodepistat 30 mg plus delamanid 300 mg plus bedaquiline 400 mg orally once daily for 14 days, or rifampicin, isoniazid, ethambutol, and pyrazinamide combination therapy [control] according to local standard of care for 20 days). The primary outcomes were safety and tolerability during and after 14 days of treatment in all participants who received any study medication and pharmacokinetics at day 1 and day 14 in participants in the quabodepistat groups with adequate data for deriving pharmacokinetics parameters. The main secondary outcome was bactericidal activity from baseline to day 14 in all eligible participants who were quantitatively culture-positive at baseline. The study was not powered for formal statistical hypothesis testing; therefore, data were summarised by treatment group with descriptive statistics. This study is registered with ClinicalTrials.gov (NCT03678688) and is closed to new participants. 98 participants were screened for entry into stage 2 of the trial between Feb 1, 2021, and Jan 27, 2022, of whom 46 were randomly assigned (14 to each quabodepistat group, 4 to the control group) and 44 received at least one dose of study medication (one patient excluded from the quabodepistat plus delamanid and quabodepistat plus bedaquiline groups). 32 (73%) of 44 participants had at least one treatment-emergent adverse event. Most events (30/32 [94%]) were mild or moderate; the most common treatment-emergent adverse events (≥2 participants; not related to study drugs) were headache (4/44 [9%]), dizziness (3/44 [7%]), abdominal pain (2/44 [5%]), pruritus (2/44 [5%]), and nausea (2/44 [5%]). Two serious adverse events were reported in two participants in the quabodepistat and bedaquiline cohort (anal abscess [n=1], pneumothorax [n=1]); both were deemed not related to study drug. Quabodepistat exposure was minimally affected by coadministration of delamanid or bedaquiline, with lower exposure in the quabodepistat and bedaquiline cohorts (maximum plasma concentration for quabodepistat plus delamanid 208 ng/mL [SD 61; n=11]; quabodepistat plus bedaquiline 175 ng/mL [31; n=10]; quabodepistat plus delamanid plus bedaquiline 183 ng/mL [52; n=11]). Maximum quabodepistat concentrations were achieved approximately 3 h after administration in all combinations. Mean elimination half-life was shorter in combinations with bedaquiline than without bedaquiline (12·3-14·5 h vs 15·2 h). Mean changes from baseline to day 14 of sputum log10 colony-forming units per mL were -2·73 (SD 1·51) for quabodepistat plus delamanid plus bedaquiline (n=12) and -2·71 (SD 0·92) for control (n=19); mean change was -2·17 (SD 1·83) in the quabodepistat plus delamanid cohort (n=11) and -1·97 (SD 1·29) in the quabodepistat plus bedaquiline cohort (n=11). In this 14-day trial, quabodepistat plus delamanid plus bedaquiline, a novel three-drug combination, appeared to be safe, well tolerated, and provided robust early bactericidal activity in adults with drug-susceptible pulmonary tuberculosis. Further evaluation is warranted. Otsuka Pharmaceutical Development & Commercialization and the Bill & Melinda Gates Foundation.

The Effect of the Continuous Care Model on Oral Health, Self-Efficacy, and Self-Care in Patients With Head and Neck Cancer Undergoing Radiotherapy: A Study Protocol for a Quasi-Experimental Study.

Head and neck cancer, with its unique challenges, often involves radiotherapy as a primary treatment. This can lead to complications affecting patients' well-being. A continuous care model offers potential benefits, but its effectiveness requires validation through rigorous studies. This protocol aims to evaluate its impact on patients undergoing head and neck cancer radiotherapy, contributing to improved care strategies and well-being. The study is a double-arm and parallel-group quasi experimental study in which a 4-week intervention will be compared with usual care. A total of 70 eligible patients with head and neck cancer who are undergoing radiotherapy will be recruited to the intervention or control group. The patients in the intervention group will receive a continues care model designed for head and neck cancer patients in four phases of Orientation, Sensitization, Control, and Evaluation. The primary outcomes include dental plaque and gingival index, which will be measured by an approved dentist using The Gingival and Quigley-Hein index. The secondary outcomes are Oral hygiene self-efficacy and Dental and Oral Health Self-Care Behavior which will be assessed by the Oral and Dental Health Self-Efficacy and Dental and Oral Health Self-Care Behavior Questionnaires. Descriptive statistics will be used to describe variables. According to the types of variables, appropriate statistical tests, including two-sample t-tests, Χ 2, analysis of covariance, or linear regression will be performed. In conclusion, this study aims to evaluate the impact of a continuous care model on head and neck cancer patients undergoing radiotherapy. Findings will contribute to enhancing care strategies and well-being in this population. The trial has been approved by the Research Ethics Committees of Zahedan University Of Medical Sciences. In this study, written consent will be obtained from all participants. The results will be presented to representative groups and published in peer-reviewed journals.

Efficacy and Safety of Biosimilar Cetuximab Versus Innovator Cetuximab in Indian Patients With Head and Neck Cancer: A Multicenter, Randomized, Double-Blind, Phase III Trial.

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer, with approximately 225,419 new cases with over 125,000 deaths annually in India. This trial compared the efficacy and safety of biosimilar cetuximab versus innovator cetuximab (IC) in combination with platinum-based chemotherapy in patients with recurrent locoregional or metastatic SCCHN. This phase III trial is a multicenter, randomized, double-blind and parallel group study performed in Indian patients with recurrent locoregional or metastatic SCCHN. Patients were randomly assigned in 2:1 ratio to receive biosimilar cetuximab and IC in combination with cisplatin and fluorouracil via intravenous infusions. The primary end points were disease control rate (DCR) and overall response rate (ORR) as per response evaluation criteria in solid tumors version 1.1. The secondary end points included pharmacokinetics (PK), immunogenicity, safety, and tolerability. Of 180 patients enrolled, 120 patients received biosimilar cetuximab and 60 patients received IC treatment. No significant statistical difference was observed in the primary outcomes between two groups. Treatment difference in DCR and ORR response was found to be -5.21 (90% CI, -8.94 to -1.48) and -4.79 (90% CI, -19.42 to 9.84), respectively, indicating noninferiority to reference product. The incidence of treatment-emergent adverse events (AEs; biosimilar cetuximab: 89.2% v IC: 91.7%; P = .8364) and serious AEs (biosimilar cetuximab: 23.3% v IC: 13.3%; P = .0603) and PK parameters were comparable between treatment groups. The immunogenicity findings showed higher incidence of anticetuximab antibodies in the biosimilar cetuximab group compared with the IC group at the end of Study. The findings of this study demonstrated noninferiority along with comparable PK, safety, and immunogenicity of biosimilar cetuximab and IC in patients with recurrent or metastatic SCCHN.