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3.6. Effects of NSDs on Variables at Week 12, as Analyzed by a Multiple Linear Regression
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PMC10574690
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3.6.1. Body Composition, Physical Performance, and Nutritional Status
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As shown in
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PMC10574690
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3.7. Odds Ratio (OR)
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NSD
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ZINC DEFICIENCY, ASMI
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Crude ORs are shown in However, the risk of a low ASMI increased after the NSD intervention in models 1 and 2. After adjusting for the baseline ASMI and other parameters in model 2, the risk of a low ASMI disappeared in model 3. Therefore, it was estimated that the higher risk of a low ASMI might be related to the significantly lower ASMI in the NSD group at the baseline.In model 3, the NSD intervention produced a lower risk of zinc deficiency.
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PMC10574690
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3.8. QOL and SF-36 Questionnaire
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PMC10574690
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3.8.1. Effects of the NSD or NE Interventions
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MH
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After 12 weeks of the intervention, the NSD group exhibited significant improvements in physical function (PF), vitality (VT), mental health (MH), and also the total score of physical health (physical component score, PCS) and total mental health (mental component score, MCS) in the SF-36 questionnaire (
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PMC10574690
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3.8.2. Changes in SF-36 Questionnaire Scores after the NSD and NE Interventions
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MH, NSD
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To evaluate changes and improvements in SF-36 scores after the intervention, we compared changes in scores of both groups by analyzing values of week 12 minus those of week 0. The NSD group had significantly greater improvements in PF, VT, social functioning (SF), MH, PCS, and MCS than the NE group (
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PMC10574690
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3.9. Correlations among the SF-36 Questionnaire, the Nutritional Status, Physical Performance, Vit. D, and the Intervention
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As shown in
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PMC10574690
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4. Discussion
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PMC10574690
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4.1. ONSs, BW, Body Composition, and Physical Performance
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NSD, NSDs
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ASMI
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The current results demonstrated that NSDs significantly increased BW and BMI (In this study, the SOF significantly decreased, and walking speed significantly increased without changing the body fat or muscle mass in the NSD group (Compared to participants who only received the NE intervention, the improved effects of the NSD intervention on increasing BW, BMI, and ASMI and decreasing the SOF and physical performance were more obvious than those of the NE intervention (
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PMC10574690
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4.2. Effects of the NSD on Related Variables
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NSDs
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REGRESSION
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Based on a multiple linear regression, NSDs showed positive effects on BW, BMI, calf circumference, walking speed, and MNA-SF scores, and negative effects on the SOF, and produced an improvement in frailty (
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PMC10574690
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4.3. Blood Albumin Levels and Related Variables
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NSD
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BLOOD
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Blood albumin levels remained within the normal range in both the NSD and NE groups, although it had significantly decreased in the NSD group after 3 months (
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PMC10574690
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4.4. Vit. D and Zn Deficiencies
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In this study, the definition of the Vit. D status was based on recommendations from the Endocrine Society Task Force on Vitamin D in the US population [The percentage of participants with a Zn deficiency was 37.3% (40/107) at the baseline in this study (
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PMC10574690
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4.5. Crude and Adjusted ORs
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NSD
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MALNUTRITION
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The crude and adjusted ORs showed risks of frailty, malnutrition, and low walking speed were significantly reduced after the NSD intervention (
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PMC10574690
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4.6. Nutritional Status and QoL
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NSDs
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Results indicated that NSDs can improve the activity and mental health of older nursing home-dwelling persons more than those who only received NE (
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PMC10574690
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4.7. Strengths and Limitations
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In this study, the statistical power was 0.99, which indicates a high possibility of identifying a true effect. Additionally, several nursing homes participated in the study. However, some limitations of this study should be addressed. First, the study was conducted between November 2021 and March 2023, when Taiwan was affected by COVID-19. To prevent the spread of COVID-19, nursing homes had strict requirements, including controlling visitor entry, weekly rapid tests on residents and caregivers, and quarantine measures. This policy and situation both limited researchers from collecting the questionnaires face-to-face with residents and may have created biases due to self-reporting of the questionnaires. Second, since the dietitian only provided a summary of total energy intake, nutrient intake details were not calculated. Third, a portable body composition scale was used in this study because it can conveniently be moved between nursing homes. Although the portable body composition scale was cited in previous studies [
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PMC10574690
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5. Conclusions
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NSD, malnutrition
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MALNUTRITION
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Current results indicated that the NSD intervention combined with NE for 12 weeks improved the nutritional status, including BW, BMI, and MNA-SF scores, as well as physical performance such as walking speed in the older population at risk of malnutrition (
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PMC10574690
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Supplementary Materials
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The following supporting information can be downloaded at: Click here for additional data file.
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PMC10574690
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Author Contributions
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Conceptualization, S.-C.Y.; methodology, S.-C.Y. and J.-R.C.; validation, Y.-H.C., S.-C.Y. and J.-R.C.; analysis and interpretation of data, Y.-H.C. and C.-Y.L.; investigation, C.-Y.L., M.-Y.D. and F.-Q.L.; resources, S.-C.Y. and C.-Y.L.; data curation, Y.-H.C. and C.-Y.L.; writing—original draft preparation, Y.-H.C. and S.-C.Y.; writing—review and editing, Y.-H.C. and S.-C.Y.; supervision, S.-C.Y.; project administration, S.-C.Y.; funding acquisition, S.-C.Y. All authors have read and agreed to the published version of the manuscript.
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PMC10574690
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Institutional Review Board Statement
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The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Taipei Medical University (TMU)-Joint Institutional Review Board (ID: N202011065, 27 January 2021) and ClinicalTrials.gov Protocol Registration and Results System (NCT04857463) “
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PMC10574690
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Informed Consent Statement
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Informed consent was obtained from all subjects involved in the study.
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PMC10574690
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Data Availability Statement
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Data available on request due to privacy/ethical restrictions.
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PMC10574690
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Conflicts of Interest
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The authors declare no conflict of interest.
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PMC10574690
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References
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Malnutrition, NSD, appendicular skeletal muscle, malnutrition
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OSTEOPOROTIC FRACTURE, MOS, MALNUTRITION, ASMI, MALNUTRITION, REGRESSION
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Study flow diagram for nutritional supplement drink or nutritional education on the nutritional status in older individuals at risk of malnutrition. MUST, Malnutrition Universal Screening Tool.Beneficial effects of a nutritional supplement drink (NSD) on the nutritional status of older individuals at high risk of malnutrition. The upward arrow represents an increase or growth, while the downward arrow represents a decrease or decline. NE, nutritional education; MUST, malnutrition universal screening tool; BW, body weight; BMI, body-mass index; ASMI, appendicular skeletal muscle index; SOF, study of osteoporotic fractures; MNA-SF, Mini-Nutritional Assessment Short Form; TGs, triglycerides; SF-36, MOS 36-Item Short Form Health Survey; PF, physical functioning; VT, vitality; MH, role emotional; PCS, physical component score; MCS, mental component score.Nutrition Facts of Meiji Mei Balance *.* Mei Balance (Meiji Holdings, Tokyo, Japan). Baseline demographic information, anthropometric assessment results, and dietary intake levels of study participants.Data are expressed as the mean ± standard deviation. The Shapiro-Wilk test was used to determine the normality of the population. Data were compared by a Effects of a nutritional supplement drink (NSD) on the body composition, physical performance, nutritional status, and nutrition intake in older nursing home residents at risk of malnutrition.Data are expressed as the mean ± standard deviation. The Shapiro-Wilk test was used to determine the normality of the population, and data were compared by a Changes in anthropometric data and the nutritional status after 12 weeks of the intervention.Data were calculated by the value of week 12—the baseline and are expressed as the mean ± standard deviation. The Shapiro-Wilk test was used to determine the normality of the population. Data were compared by a Effects of nutritional supplement drink (NSD) on the plasma vitamin (Vit.) D and zinc status in older nursing home residents at risk of malnutrition.Data are expressed as numbers and percentages. Frequencies between groups were compared by Fisher’s exact test or a Chi-squared test. NE, nutritional education. 25-OH Vit.D, 25-Hydroxyvitamin D.Effects of a nutritional supplement drink on the body composition, physical performance, nutritional status, and nutrition intake of older nursing home residents at risk of malnutrition by multiple linear regression.Data were analyzed by multiple linear regression and were adjusted for age, baseline BW, and baseline BMI. BW, body weight; BMI, body mass index; ASMI, appendicular skeletal muscle index; SOF, study of osteoporotic fractures; SBP, systolic blood pressure; DBP, diastolic blood pressure; MNA-SF, Mini-Nutritional Assessment Short Form.Effects of a nutritional supplement drink on biochemical parameters in older nursing home residents at risk of malnutrition by multiple linear regression.Data were analyzed by a multiple linear regression and were adjusted for age, baseline body weight, and baseline body-mass index. ALT, alanine aminotransferase; AST, aspartate aminotransferase; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; RBCs, red blood cells; TC, total cholesterol; TIBC, total iron-binding capacity; WBCs, white blood cells; RDW-CV: red blood cell distribution width.Crude and adjusted odd ratios (ORs) (95% confidence intervals (CIs)) of variables related to oral nutritional supplement drink administration in older nursing home residents at risk of malnutrition in the 12th week.Data were analyzed by a logistic regression. Model 1 was adjusted for age and sex, model 2 was adjusted for age, sex, and baseline body-mass index (BMI), and model 3 was adjusted for age, sex, baseline BMI, and baseline appendicular skeletal muscle index (ASMI). SOF, the study of osteoporotic fractures; MNA-SF, Mini-Nutritional Assessment Short Form. Normal range of calf circumference, Males > 34 cm, Females > 33 cm; normal range of hemoglobin, Males 12.3~18.3 g/dL, Females 11.3~15.3 g/dL; normal range of ASMI, Males ≥ 7.0 (kg/m
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PMC10574690
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Methods:
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treatment-emergent adverse, Attention-Deficit/Hyperactivity Disorder
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In this study, a 5-week, open-label dose-optimization period (DOP) preceded a 2-week, randomized, crossover double-blind treatment period (DBP). Eligible patients received d-ATS 5 mg during the DOP, with weekly evaluations for increase to 10, 15, and 20 mg (equivalent to labeled doses of 4.5, 9, 13.5, and 18 mg/9 hours, respectively) until reaching and maintaining the optimal dose, which was utilized for the DBP. Secondary endpoints included assessment of Attention-Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV), Conners' Parent Rating Scale Revised Short Form (CPRS-R:S), and Clinical Global Impression (CGI) scores. NNT was calculated for ADHD-RS-IV and CGI-Improvement (CGI-I). Safety assessments included treatment-emergent adverse events (TEAEs) and dermal safety.
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PMC10282809
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Results:
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In total, 110 patients entered the DOP, with 106 patients randomized (DBP). During the DBP, the least-squares mean (95% confidence interval) difference for d-ATS versus placebo in ADHD-RS-IV total score was −13.1 (−16.2 to −10.0;
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PMC10282809
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Conclusions:
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ADHD
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SECONDARY
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d-ATS was effective in treating ADHD in children and adolescents, meeting all secondary endpoints, with a large effect size and NNT of 2–3 to achieve a clinically meaningful response. d-ATS was safe and well tolerated, with minimal dermal reactions.
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PMC10282809
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Clinical Trial Registration:
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NCT01711021.
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PMC10282809
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Introduction
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Psychiatric, Attention-deficit/hyperactivity disorder, hyperactivity/impulsivity, Attention Deficit/Hyperactivity Disorder, ADHD, neurodevelopmental disorder
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DIFFICULTY SWALLOWING, SECONDARY
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Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder characterized by persistent inattention and/or hyperactivity/impulsivity that interferes with function or development and negatively impacts social, academic, and occupational activities (American Psychiatric Association, 2013; Bélanger et al., Stimulants such as methylphenidate and amphetamine are recognized as the most commonly prescribed and effective treatments for ADHD in children and adolescents (Cortese et al., Transdermal formulations offer a number of features that patients and caregivers may view as advantages over oral formulations, including easier treatment of individuals who have difficulty swallowing oral medications, potential for fewer gastrointestinal side effects, flexibility in treatment duration by varying patch wear times, and visual confirmation of adherence to treatment (Findling and Dinh, The dextroamphetamine transdermal system (d-ATS) was developed as an alternative to oral amphetamine formulations and is the first and only transdermal amphetamine patch approved by the Food and Drug Administration (FDA) for use in adults and pediatric patients (children and adolescents) 6 years and older (Noven Therapeutics, 2022).A pivotal randomized controlled trial of d-ATS in children and adolescents with ADHD was conducted, and its primary endpoint (efficacy of d-ATS compared with placebo, as measured by the Swanson, Kotkin, Agler, M-Flynn, and Pelham scale [SKAMP] total score) and key secondary endpoints were met (Cutler et al., When considering treatment options for ADHD, clinicians must weigh the potential benefit of a given treatment, which is generally indicated by response, against its potential risks, such as safety and/or tolerability issues. Measures such as effect size and number needed to treat (NNT) can be used to quantify these potential benefits by providing clinical meaningfulness to changes in rating scale scores. Effect sizes estimate the efficacy of an active intervention to quantify and communicate the clinical relevance of statistically significant trial results. Cohen's effect size for comparison between two groups (active vs. placebo) is classified as small (0.20), medium (0.50), or large (0.80) (Cohen, To further assess the efficacy and safety of d-ATS in the treatment of 6–17-year-old children and adolescents with ADHD in a randomized laboratory classroom study, we report additional secondary endpoints from the pivotal study, including Attention Deficit/Hyperactivity Disorder Rating Scale IV (ADHD-RS-IV), Conners' Parent Rating Scale Revised Short Form (CPRS-R:S), and Clinical Global Impression-Improvement (CGI-I) and -Severity (CGI-S) scores. In a
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PMC10282809
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Methods
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PMC10282809
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Patients and study design
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UC
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The study described herein was approved by the Western Institutional Review Board and the UC Irvine Institutional Review Board. This study included a 5-week, open-label dose-optimization period (DOP) followed by a 2-week, randomized, crossover double-blind treatment period (DBP), with details reported previously (Cutler et al., After a 3-day washout period, all eligible patients entered the 5-week DOP, which evaluated 4 doses of d-ATS: 5, 10,15, and, 20 mg (equivalent to approved doses of 4.5 mg/9 hours, 9 mg/9 hours, 13.5 mg/9 hours, and 18 mg/9 hours, respectively) (Xelstrym Prescribing Information,
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PMC10282809
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Study assessments
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ADVERSE EVENTS, SECONDARY
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Secondary objectives for this study included assessment of efficacy through the ADHD-RS-IV scale, CPRS-R:S scale, and CGI-I and CGI-S scores. Analysis of these secondary assessments was performed on the Full Analysis Set, which included all randomized patients who received at least one dose of study medication.Safety outcomes, including treatment-emergent adverse events (TEAEs) and dermal safety, were based on the Safety Population, which included all subjects who took at least one dose of study medication and had at least one postdose safety measurement (including dermal assessments).
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PMC10282809
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Statistical analysis
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hyperactivity, impulsivity
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LS means, 95% CIs, and Model-based LS mean effect sizes were assessed for ADHD-RS-IV total score and the inattention and hyperactivity–impulsivity subscale scores NNT was calculated
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PMC10282809
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Results
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PMC10282809
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Baseline characteristics
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In total, 110 subjects were enrolled in the DOP, with optimized doses achieved for 107 patients. The Details of the demographics and baseline characteristics for the population have been reported in detail previously. Briefly, 69% of patients were male, and weight, height, and body mass index were balanced across treatment sequence groups. Mean (standard deviation [SD]) baseline ADHD-RS-IV total score for the Safety Population (all patients receiving at least one dose of study medication and having at least one postdose measurement) was 38.3 (8.6), assessed before the start of the DOP (Cutler et al.,
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PMC10282809
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Safety
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Safety outcomes have been reported in detail previously (Cutler et al.,
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PMC10282809
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Discussion
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ADHD
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SECONDARY
|
The reported data indicate that d-ATS was effective in the treatment of ADHD in children and adolescents, meeting all secondary endpoints. Throughout the DOP, treatment with d-ATS resulted in consistent improvement as measured by ADHD-RS-IV score, with a significant improvement versus placebo observed during the DBP. A significant difference between placebo and d-ATS treatment was also observed on the CPRS-R:S scale during the DBP, and significantly more patients treated with d-ATS versus placebo were considered responders according to the CGI-I scale. As reported previously, d-ATS met its primary endpoint in a pivotal phase 2 study, resulting in significant improvement versus placebo in ADHD symptoms from 2 through 12 hours postdose, as measured by SKAMP total score (Cutler et al., d-ATS has been observed to be safe and well tolerated. A systemic safety profile consistent with oral amphetamines was observed, according to this and previous reports (Cutler et al., These efficacy results are also supported by a The NNT values calculated for the selected endpoints indicate the clinical relevance of d-ATS treatment. Only three patients needed to be treated with d-ATS instead of placebo to observe one additional patient achieving a clinically meaningful change, that is, a 50% or greater reduction from baseline in ADHD-RS-IV score. Only two patients needed to be treated with d-ATS instead of placebo to observe one additional patient experiencing “much improved” or “very much improved” ADHD symptoms, as measured by CGI-I scores.The observed d-ATS efficacy is comparable to oral preparations of amphetamine and methylphenidate, with an observed effect size and NNT similar to those reported elsewhere. In a study investigating the efficacy of oral lisdexamfetamine and osmotic-release oral system methylphenidate in children and adolescents with ADHD, effect sizes for LS mean change in ADHD-RS-IV total score versus placebo were 1.80 and 1.26, respectively (Soutullo et al., One limitation of this study is its relatively short duration. Furthermore, the classroom setting does not perfectly replicate a typical elementary or secondary classroom, which limits the generalizability of the results. Although a carryover effect was investigated for the primary endpoint (Cutler et al., This analysis defined ≥30% as the lower threshold for ADHD-RS-IV response; however, some patients achieving a 30% change in ADHD-RS-IV score, particularly those with severe symptoms at baseline, may not experience clinical improvement (i.e., a CGI-I response) (Weiss et al., Transdermal delivery has the potential to provide several advantages over oral medications, including avoiding gastrointestinal side effects, allowing flexibility in treatment duration, providing an additional treatment option for patients who may not be able or willing to swallow medications, and enabling a simple visual check for treatment compliance (Findling and Dinh,
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PMC10282809
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Conclusion
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ADHD
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d-ATS represents an important innovation for the known population of patients with ADHD who respond better to amphetamine than methylphenidate (Arnold,
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PMC10282809
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Clinical Significance
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ADHD
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NERVOUS SYSTEM DISORDERS
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Methylphenidate and amphetamines have shown high efficacy in treating ADHD in children and adolescents; however, approximately 40% of patients with ADHD respond to only one of these drugs, indicating the need for additional treatment options, including multiple formulations. Although transdermal therapies have numerous advantages in the treatment of nervous system disorders, only one FDA-approved transdermal treatment (methylphenidate) for ADHD in children and adolescents is currently available.
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PMC10282809
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Acknowledgments
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The authors thank Michelle Jones, PhD, MWC and Anthony DiLauro, PhD of PharmaWrite, LLC, for medical writing and editorial assistance, which were funded by Noven Pharmaceuticals, Inc. This article was prepared according to the International Society for Medical Publication Professionals' “Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3.”
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PMC10282809
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Authors' Contributions
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All authors were actively involved in study design, data acquisition, or data analysis/interpretation, and in drafting or critically revising the article. All authors reviewed the final article and gave approval for submission.
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PMC10282809
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Disclosures
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A.J.C. reports personal fees from AbbVie, Acadia, Alfasigma, Alkermes, Attentive, Corium, Intracellular Therapies, Ironshore, Janssen, Lundbeck, MedAvante-ProPhase, Neurocrine, Neuroscience Education Institute, Noven, Sunovion, Takeda, and Teva; grants from Arbor, Axsome, Biohaven, KemPharm, Novartis, and Purdue; grants and personal fees from Akili Interactive, Axsome, Otsuka, Sage, Supernus, and Tris Pharma; and data safety monitoring board for Cognitive Research, outside the submitted work. K.S., B.S., K.B., M.K., S.M., and M.C. report nonfinancial support during the conduct of the study and personal fees outside the submitted work from Noven Pharmaceuticals, Inc. A.C. reports research funding from Akili Interactive, Allergan, Arbor, Emalex, Ironshore, KemPharm, Lumos, Neos Therapeutics, Otsuka, Pfizer, Purdue, Rhodes, Servier, Sunovion, Supernus, Takeda (Shire), and Tris Pharma; consultancy/advisory role with Aardvark, Adlon, Akili Interactive, Arbor, Aytu, Cingulate, Corium, Ironshore, Jazz, KemPharm, Lumos, Medison Pharma, Neos Therapeutics, Neurocentria, Noven, Otsuka, Pfizer, Purdue, Rhodes, Sky, Sunovion, Supernus, Takeda (Shire), Tris Pharma, and Tulex; speakers' bureau for Arbor, Corium, Ironshore, Neos Therapeutics, Pfizer, Supernus, Takeda (Shire), and Tris Pharma; and nonfinancial support from Arbor, Ironshore, Neos Therapeutics, Noven, Pfizer, Purdue, Rhodes, Sunovion, Takeda (Shire), and Tris Pharma.
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PMC10282809
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References
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PMC10282809
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Purpose
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chronic open-angle glaucoma, OAG
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This study aims to evaluate whether the use of citicoline oral solution could improve quality of life in patients with chronic open-angle glaucoma (OAG).
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PMC10199108
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Design
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Randomized, double-masked, placebo-controlled, cross-over study was used. Patients were randomized to one of the two sequences: either citicoline 500 mg/day oral solution-placebo or placebo-citicoline 500 mg/day oral solution. Switch of treatments was done after 3 months; patients were then followed for other 6 months. Follow-up included 3-month, 6-month, and 9-month visits.
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PMC10199108
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Outcomes
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The primary outcome was the mean change of “intra-patient” composite score of the Visual Function Questionnaire-25 (VFQ-25)
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PMC10199108
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Methods
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visual field damage, OAG
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EYE
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The trial was multicenter, conducted at 5 European Eye Clinics. OAG patients with bilateral visual field damage, a mean deviation (MD) ranging from − 5 to − 13 dB in the better eye, and controlled IOP were included. VFQ-25 and SF-36 questionnaires were administered at baseline and at 3-, 6-, and 9-month visits. A mixed effect model, with a random effect on the intercept, accounted for correlations among serial measurements on each subject.
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PMC10199108
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Results
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The primary pre-specified outcome of the analysis reached statistical significance (
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PMC10199108
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Conclusions
|
glaucomatous
|
This is the first placebo-controlled clinical study evaluating the effect of a medical treatment aiming at improving vision-related quality of life in glaucomatous patients.
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PMC10199108
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Supplementary Information
|
The online version contains supplementary material available at 10.1007/s00417-022-05947-5.
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PMC10199108
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Keywords
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Open access funding provided by Università degli Studi di Milano within the CRUI-CARE Agreement.
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PMC10199108
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Introduction
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Open-angle glaucoma, senile dementia, OAG
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PROGRESSIVE OPTIC NEUROPATHY, BLINDNESS, DISEASE, SENILE DEMENTIA, NEURODEGENERATIVE DISEASES, OPEN-ANGLE GLAUCOMA, VISUAL IMPAIRMENT
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Open-angle glaucoma (OAG) is a progressive optic neuropathy and one major cause of global blindness [Visual impairment is commonly associated with the disease, particularly with more advanced stages [Treatment of the disease has the objective of slowing (or stopping) progression of damage to maintain vision-related quality of life for as long as possible [Citicoline is a molecule that has been extensively studied in neurodegenerative diseases. A number of reports on both experimental and clinical findings have been published in the last decades on senile dementia [To test the effect of citicoline oral solution on quality of life in patients with chronic OAG, we conducted a multicenter, randomized, placebo-controlled cross-over study.
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PMC10199108
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Methods
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-11, EYE
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The trial was conducted at 5 University Eye Clinics in Rome, Barcelona, Leuven, Thessaloniki, and Milan between winter 2019 and summer 2021. The study was designed following the tenets of the Declaration of Helsinki, and the protocol was submitted and approved by each University Ethics Committee. The trial was funded by Omikron Italia®a srl and registered (EudraCT 2018–002187-11, clinicaltrials.gov).
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PMC10199108
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Patients in the trial
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VF, pigmentary glaucomas, glaucomatous, visual field damage, stroke, pseudoexfoliative, dementia, Parkinson’s disease, Glaucoma, OAG, glaucoma, glaucomatous damage, VF damage
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PIGMENTARY GLAUCOMA, STROKE, OPTIC NERVE, GLAUCOMA, GLAUCOMA
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Glaucoma definition was based on VF damage (24–2 SITA standard strategy, Humphrey Visual Field Analyser, HFA) corresponding to glaucomatous changes at the optic nerve head (ONH) irrespective of IOP. Inclusion criteria were patients with OAG, including pseudoexfoliative and pigmentary glaucomas; age ≥ 18 years; presence of bilateral visual field damage; a level of moderate damage in the better eye, with a mean deviation (MD) ranging from − 5 to − 13 dB at the screening assessment; controlled IOP (according to physician’s judgement); and a signed consent form to participate in the study. Exclusion criteria were single-eyed patients; patients without those psychophysical requirements to adequately participate and complete the trial; patients with other types of glaucoma; patients with other ocular comorbidities interfering with the correct assessment of the glaucomatous damage to the VF; patients who had undergone surgery within 6 months; patients taking other potential neuroprotectors; patients with Parkinson’s disease, dementia or a diagnosis of stroke in the last 6 months.
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PMC10199108
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Study design
|
VF
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TREATMENT SIDE EFFECTS, LENS
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The trial was a randomized, double-masked, placebo-controlled, cross-over study. Patients who accepted to participate in the trial signed an informed consent form and were randomized to one of the two sequences of the cross-over design: either citicoline 50 mg/ml oral solution-placebo or placebo-citicoline 50 mg/ml oral solution. The randomization was stratified by center.The study protocol included the following visits:Baseline visit (beginning of 1st period): Patients underwent a complete ophthalmic examination, including BCVA, biomicroscopy (with a specific lens evaluation using the Lens Opacities Classification System III, LOCS III, criteria [3-month visit (end of the 16-month visit: Patients were asked again about treatment side effects, and all complains/considerations were recorded. Patients were again administered the 2 study questionnaires (SF-36 and VFQ-25). A complete ophthalmic examination and a VF test with the same strategy were performed. Patients received the assigned bottles for the third 3-month phase.9-month visit (end of the 2st period): Patients were asked again about treatment side effects and administered the two study questionnaires (VFQ-25 and SF-36). A final, complete ophthalmic examination and a VF test with the same strategy were performed.
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PMC10199108
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Study treatments
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Neurotidine®
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DISEASE
|
Patients were treated with any IOP-lowering agent to control the disease. Patients were randomized to a citicoline 50 mg/ml oral solution-placebo or placebo-citicoline 50 mg/ml oral solution sequence and received treatment for 3 months in the first period and for 6 months in the second period of the cross-over design. The second period was extended to 6 months to control for a potential carry-over effect in the group receiving citicoline oral solution in the first period of the cross-over design.Two identical bottles contained either 500 ml of citicoline oral solution (Neurotidine®, Omikron Italia srl), citicoline free acid 50 mg/ml; water; fructose; acidity regulators: sodium citrate, sodium hydroxide; preservative: potassium sorbate; color: riboflavin; or placebo 500 ml oral solution, water; fructose; sucralose; acidity regulators: sodium citrate, anhydrous citric acid, sodium hydroxide; preservative: potassium sorbate; color: riboflavin. Citicoline oral solution or placebo were administered at a dosage of 10 ml (500 mg of citicoline/day) in the morning.
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PMC10199108
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Study outcomes
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The primary outcome was the mean change of “intra-patient” global score of the VFQ-25 questionnaire after citicoline oral solution vs placebo at 6 months as compared with baseline. Secondary outcomes were the difference in the change from baseline at 3 and 9 months; the comparison between different time-points in each arm with the respective baseline; the comparison between the two arms at each time-point of the two study questionnaires, VFQ-25 and SF-36, and the safety and tolerability of citicoline oral solution.
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PMC10199108
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Analysis
|
The trial sample size was calculated on the main outcome of the study. With a sample size in each sequence group of 100 (a total sample size of 200), a 2 × 2 crossover design would have 80% power to detect a difference in mean intra-patients global score of 3.0 assuming that the crossover ANOVA √MSE is 10.607 (the standard deviation of differences, σd, is 15.0) with a 0.05 two-sided significance level. The total sample size was adjusted to 220 patients considering an expected dropout rate of about 10%.The primary outcome analysis was performed on the composite score of the Visual Function Questionnaire-25 (VFQ-25) [
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PMC10199108
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Results
|
INTRAOCULAR PRESSURE
|
One-hundred-fifty-five patients were included in the study. Four patients were excluded because not properly randomised. Four patients from the citicoline oral solution-placebo arm and one from the placebo-citicoline oral solution arm were excluded because they did not complete any visit beyond the baseline, as reported in the CONSORT flow diagram (Supplementary Fig. Descriptive statistics at baseline, reported as median [interquartile range] for continuous values. BCVA = best corrected visual acuity; MD = mean deviation; RNFL = retinal nerve fiber layer; VFQ = Visual Function Questionnaire; SF = Short Form health survey. RNFL thickness and intraocular pressure are for the better eye. *One female subject missingGraphical representation of the results in Table Results of the sequence analysis at different time points. The table reports the estimate [95% confidence intervals] of the composite score from the model. The Bold: Graphical representation of the results in Table The results of subscale score analysis are reported in Fig. Sequence analysis for each subscale in the VFQ-25 questionnaire. The dots represent the estimates from the model; the error bars represent the 95% confidence intervalsOverall, both placebo and citicoline oral solution had a significant effect compared to no treatment (i.e., to baseline, see Fig. Results of the treatment analysis. The table reports the estimate [95% confidence intervals] of the composite score from the model. The Bold: A mixed effect model was used to explore the effect of the baseline composite score on the change obtained with the placebo and citicoline oral solution respectively. The differential effect of the treatment was modelled through an interaction term between the treatment and the baseline composite score. If significant, this indicates a significant difference in the effect of citicoline oral solution compared to placebo at the same baseline score. The Change from baseline obtained with citicoline oral solution and placebo stratified by baseline composite scoreA model similar to the one for the baseline score was used to study the correlation between the mean deviation (MD) of the better eye and the composite score. MD had a significant effect on the composite score (The analysis of SF-36 questionnaire was conducted using the same approach as the VFQ-25. The only difference was that the two main summary scales, the mental component, and physical component summary, needed to be kept as separate scores. The estimates of the model for the main outcome are reported in Table Results of the sequence analysis at different time points. The table reports the estimate [95% confidence intervals] of the composite score from the model. The Results of the treatment analysis. The table reports the estimate [95% confidence intervals] of the composite score from the model. The Bold:
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PMC10199108
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Discussion
|
glaucomatous, VF damage, glaucoma
|
DISEASE, RECRUITMENT, NEURODEGENERATIVE DISEASES, SECONDARY, GLAUCOMA
|
This is the first placebo-controlled clinical study evaluating the effect of a medical treatment aiming at improving vision-related QoL in glaucomatous patients. The primary pre-specified outcome of the analysis (difference in the change from baseline at six months) reached statistical significance (Citicoline oral solution did not show any significant effect on the general quality of life (SF-36) which also showed poor correlations with metrics of visual function. The fact that only the visual questionnaire (VFQ-25) and not the general health questionnaire (SF-36) showed a significant improvement suggests that the citicoline effect was more related to visual function than just to the general health status in our study involving glaucoma patients.There is a copious literature supporting citicoline effect in glaucoma and more in general in neurodegenerative diseases [The findings of our trial confirm the effect of citicoline as a neuroenhancer as the short duration of the study did not allow to show any significant disease change. Data on visual field confirm that no progression occurred in the 9-month follow-up time. The “good IOP control” (i.e., 13 mmHg on average in both groups) reinforces the likelihood of a lack of progression in these patients. In fact, differently from what could be observed in another trial, this sample was not selected based on glaucoma progression despite IOP control [Among study limitations, it is worth mentioning the reduced sample size of the study. Of the 220 patients that were planned, only 155 were finally enrolled. The drop-out rate was low (5%), less than predicted, despite the trial period fell completely into “pandemic time.” Average values of composite score in the 2 arms showed that overall quality of life was rather good, similar to the one observed in other clinical trials including patients with moderate glaucoma. It is possible that the reduced statistical power of the study did not allow to find differences in secondary outcomes between citicoline and placebo; and the same comment holds for subscales analyses. Another possible limitation is the lack a of wash-out period between the 2 cross-over phases. We do not think it has had a meaningful impact on our results, as confirmed by the lack of significant differences between the 6-month and 9-month time-points. However, any potential carry-over effect would have acted to dilute the difference between the two arms after the switch, potentially reducing the chances of detecting a significant change from baseline, but this was not the case.To conclude, this trial supports the effect of citicoline oral solution on improving the vision related quality of life, measured by the VFQ-25, with no positive or negative impact on the general quality of life, measured by the SF-36. The VFQ-25 composite score at baseline was generally high, making harder to show an impact of glaucoma on quality of life in the study population. Future investigations should focus on the recruitment of participants with more advanced bilateral VF damage, in whom a compromised quality of life can be more likely observed.
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PMC10199108
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Funding
|
Open access funding provided by Università degli Studi di Milano within the CRUI-CARE Agreement. The trial was funded by Omikron Italia, and registered (NCT04046809, clinicaltrials.gov).
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PMC10199108
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Declarations
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PMC10199108
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Ethics approval
|
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committee of each University involved in the trial, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
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PMC10199108
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Conflict of interest
|
LR, FG, GM, IS, FT, and GM are consultants for Omikron Italia srl.
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PMC10199108
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References
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PMC10199108
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2. Materials and Methods
|
paresis of the upper extremities, Stroke, stroke, ischemic stroke, dizziness, motor impairment, febrile
|
STROKE, STROKE, ISCHEMIC STROKE
|
The double-blind, randomized, placebo-control research was conducted at the Clinic for Rehabilitation “Dr. Miroslav Zotovic” in Belgrade over three years from March 2019 to March 2022. The design of this study was the double-blind because neither patients nor the data collectors know which treatment the patients were receiving until the study was over. The study included 110 patients of both sexes of at least 18 years of age with neuroradiologically confirmed ischemic stroke and severe motor impairment (National Institutes of Health Stroke Scale (NIHSS) >14) [The criteria for inclusion of patients in the study were the following: (a) the first stroke in a subacute phase (7–14 day lapse from the insult); (b) stroke of cortical or subcortical localization verified by computerized tomography or nuclear magnetic resonance imaging; (c) patients with unilateral paresis of the upper extremities of a severe degree (FME-UE ≤ 25) [Of a total of 112 patients assessed for eligibility, 60 patients met the criteria and entered the study. All of the examined patients were inpatients undergoing rehabilitation treatment, and all were subjected to thorough anamnesis, laboratory, and clinical evaluation. The total number of patients excluded from the study was 52. The number of participants who failed to meet the inclusion criteria was 27. The number of those excluded due to comorbidities that made it impossible to carry out the treatment (frequent oscillations of blood pressure, dizziness in an upright position, or febrile conditions) was 13. Twelve patients declined to participate.All participants signed an informed consent that allowed for their participation in the research, which the Clinic’s Ethics Committee approved (No. 03-1518).
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PMC9958781
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2.1. Sample Size
|
To determine the needed sample size, a two-tailed independent
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PMC9958781
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2.2. Interventions
|
The patients were allocated randomly into two groups using 60 sequentially numbered, opaque, sealed envelopes that had been prepared earlier using a computerized table of random numbers (using RSudio), and which were balanced to ensure equal numbers in each group. The allocations were concealed from the statistician until the statistical analysis had been completed. Significant heterogeneity exists amongst the studies regarding time of treatment initiation, treatment dosage, and duration. In our study, the dosage of Cerebrolysin was based on previously published data from a meta-analysis of nine randomized trials evaluating Cerebrolysin’s clinical efficacy compared to a placebo. Treatment efficacy was demonstrated primarily with daily 30 mL Cerebrolysin infusions for 10 or 21 days when initiated within 12 to 72 h of symptom onset [
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PMC9958781
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2.3. Safety Criteria
|
ADVERSE EFFECTS
|
The rehabilitation protocol was carried out individually for all patients under the supervision of a physio and occupational therapist with a graduate degree and vast experience in neurological rehabilitation. Clinicians had performed laboratory tests and medical evaluations at the beginning of the study, and at least once a week during inpatient rehabilitation, as well as at the end of the study (90 days from start of the rehabilitation). In addition, all subjects were asked about any new symptoms in order to identify the adverse effects of treatment.
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PMC9958781
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2.4. Outcome Measures
|
sensory loss, dysarthria, neurological disease, Stroke, stroke, ataxia, upper extremity motor impairment, visual-field loss
|
STROKE, NEUROLOGICAL DISEASE, STROKE
|
Stroke severity was recorded using the NIHSS through 15 items on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. Items were scored on a 3- to 5-point scale, with a maximum total score of 42 points. According to the NIHSS, stroke severity levels may be stratified as follows: very severe: >25; severe: 15–24; mild to moderately severe: 5–14; mild: 1–5 [The primary outcome for evaluating upper limb recovery was the Action Research Arm Test (ARAT), as it values functional recovery of the arm through coordination, dexterity, and upper extremity function. The subject is seated upright in a chair with a firm back and no armrests for the test’s administration [Secondary outcomes were the Fugl-Meyer assessment score (FMA) and the Barthel Index (BI). The FMA is used to assess upper extremity motor impairment. A widely used FMA subscale for the assessment of motor function is the FMA-UE motor score, which assesses voluntary and synergistic movements of the upper extremity through evaluating the upper extremity as a whole, in addition to wrist, hand and coordination/speed. The body function test is scored on a three-point ordinal scale, and item scores are summed to provide a maximum score of 66 [The BI assesses ADL. It includes ten items of ADL, and all items are rated based on the amount of assistance required to complete each activity. The items bathing and grooming are scored 0 or 5; the items feeding, dressing, controlling the bladder, controlling the bowel, getting on and off the toilet, and ascending and descending stairs are scored as 0, 5, or 10. Items for transferring from a wheelchair to the bed and walking on a level surface are scored as 0, 5, 10, or 15. The maximum score is 100, which corresponds to complete independence, and the minimum score is 0, corresponding to total dependence [All outcomes were evaluated at baseline (start of the treatment), after the intervention (immediately after the treatment on day 21), and on the 90th day of rehabilitation treatment by a physiotherapist experienced in the rehabilitation of neurological disease patients who were blinded to group assignment.
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PMC9958781
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2.5. Statistical Analysis
|
To test for the effects of Cerebrolysin across all time points (pre-therapy, post-therapy, and after 90 days), we used a two-way repeated measures analysis of variance (ANOVA) with time and groups as the within-patient factor and the between-patient factor, respectively, when the conditions were fulfilled. Otherwise, a robust two-way repeated measures analysis of variance with time as a group factor was used. The generalized Eta-Squared was used as a measure of effect size, with an interpretation small closer value of 0 and a large closer value of 1.The one-way repeated ANOVA was used when the conditions were fulfilled to test the changes in the outcome measures over time within each group separately. Otherwise, the Friedman test was used. Within ANOVA, multi-comparisons were conducted using a paired The assumption of sphericity was tested by the Mauchly’s test. In cases when the assumption of sphericity has been violated, the Sphericity corrections were used. The Greenhouse–Greisser (GG) and the Huynh–Feldt (HF) were used for adjusting the degrees of freedom from the repeated measures ANOVA. If the GG value was greater than 0.75, the HF value was used.The assumptions related to approximately normally distributed data at each time point were tested using the Shapiro–Wilk test and normal QQ plots.The independent A statistical analysis was conducted in RStudio (version 1.4.1106). The basic level of statistical significance was set at 0.05.
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PMC9958781
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3. Results
|
post-stroke hemiparesis
|
ADVERSE EVENTS
|
One hundred and twelve patients with severe post-stroke hemiparesis were screened for eligibility criteria. Sixty patients fulfilled all eligibility criteria. Twenty-seven did not meet the inclusion criteria, thirteen patients were medically unstable, and twelve declined to participate in the clinical trial. There were no significant differences in baseline demographic and clinical parameters between groups. Descriptive statistics of all outcomes in both groups are presented in Thirty participants were included in each group. There was no statistically significant difference in sex (The results of testing the changes in the outcome measures (NIHSS, BI, FMA-UE, and ARAT) over time are presented in There is a statistically significant two-way interaction between the type of therapy and time for all outcomes (NIHSS: F (2.58) = 56.1, The changes in outcome measures over time at each level of treatment are statistically significant in all outcomes for the Cerebrolysin group (The changes in the outcome measures over time at each level of treatment are statistically significant in all outcomes (At different time points, all tested parameters differed significantly in the Cerebrolysin group. The BI, FMA-UE, and ARAT were statistically significantly higher (BI: < 0.0001; FMA-UE: The changes in the outcome measures over time at each level of treatment were statistically significant in all outcomes for the placebo group (At different time points, all tested parameters differed significantly in the placebo group. BI, FMA-UE, and ARAT were statistically significantly higher (BI: Both groups showed a significant improvement over time in the BI, FMA-UE, ARAT, and NIHSS scores. However, the participants receiving Cerebrolysin therapy made more significant improvement than participants in the placebo group (The significant improvement between two time points in all outcomes of both groups, separately, is presented in Statistically significant differences were shown between the Cerebrolysin and placebo groups in all tested parameters at different time points (NIHSS: pre–post: The comparisons in time points between groups in NIHSS score, Barthel index, FMA-UE and ARAT are presented in There is no statistically significant difference between groups in the Barthel Index in time point post. All other comparisons between groups are statistically significant with a large effect size, except the NIHSS score with a medium effect size.No adverse events were registered in either group during or after the application or until the end of the study. No participant dropped out of the study.
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PMC9958781
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4. Discussion
|
subacute stroke stage, post-stroke, upper extremity motor impairment, motor impairment, acute ischemic stroke, sub-acute stroke
|
The present study aimed to investigate the effects of a three-week intravenous administration of Cerebrolysin added to the conventional rehabilitation treatment of patients at the early stage of severe sub-acute stroke compared to rehabilitation treatment only. This study’s results have shown that adding Cerebrolysin reduced paretic upper extremity motor impairment and improved functional ability better than rehabilitation treatment alone.We included patients with severe motor impairment in the early subacute post-stroke phase. Based on animal models and human studies, the data suggest that the subacute stroke stage is characterized by heightened plasticity and neural reorganization, and presents the most critical period for modification by rehabilitation treatment [In our study, the Cerebrolysin group showed a 2.6 (±1.1)-point improvement in NIHSS score after the therapy and a 5.6 (±1.5)-point improvement in the mean NIHSS score at 90-day follow-up; the placebo group only showed 1.6 (±0.7)-point improvement after the therapy and a 3.0 (±0.8)-point improvement after the 90-day follow-up. Additionally, a meta-analysis of nine randomized trials by Bornstein NM and colleagues demonstrated the treatment efficacy of Cerbolysin compared to placebo through changes in NIHSS greater than four points or the resolution of symptoms [However, some clinical studies have reported mixed evidence of Cerebrolysin’s benefit in improving recovery in acute ischemic stroke and safety characteristics. A recent meta-analysis [
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PMC9958781
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Study Limitations
|
cognitive and social status
|
ADVERSE EFFECTS, DISEASE
|
Several limitations should be considered when interpreting the results of this study. We did not consider factors that can affect the rehabilitation outcome, such as the side and localization of the lesion, motor network plasticity using functional neuroimaging, the presence of comorbidities, or the patient’s cognitive and social status. Another limitation of the study is that the results refer to patients with strict criteria for entering the study regarding disease severity. The duration of rehabilitation treatment for an individual patient is not registered but is given as an approximate minimum and maximum time. A limitation of the study is that no adverse effects were monitored after 90 days. The quality of life assessment was not considered in the current experimental design despite a longitudinal assessment of motor outcome measures after the infusion of Cerebrolysin. Furthermore, no direct assessment of the neurological outcomes, nor paretic versus non-paretic limb performance, was incorporated in the current experimental design.
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PMC9958781
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Author Contributions
|
Conceived and designed the experiments: S.Z.M., L.M.K., O.C.D. Performed the experiments: S.Z.M., O.C.D., S.D.-D., L.M.K. Analyzed the data: V.M.J., S.Z.M., L.M.K., and O.C.D. Prepared graphic representation of data: V.M.J. Contributed reagents/materials/analysis tools: S.Z.M., O.C.D., S.D.-D., L.M.K. Wrote the paper: S.Z.M., L.M.K. and O.C.D. All authors have read and agreed to the published version of the manuscript.
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PMC9958781
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Institutional Review Board Statement
|
The study was conducted according to the guidelines of the Declaration of Helsinki. The Ethics Committee of the Clinic for rehabilitation “Dr. Miroslav Zotović” approved this study (No.03-1518, 12 September 2016).
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PMC9958781
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Informed Consent Statement
|
Informed consent was obtained from all subjects involved in the study.
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PMC9958781
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Data Availability Statement
|
The data that support the findings of this study can be found in the medical system of the Clinic for rehabilitation “Dr. Miroslav Zotović” and are available from the corresponding author upon reasonable request.
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PMC9958781
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Conflicts of Interest
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The authors declare that they have no conflicts of interest.
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PMC9958781
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References
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Stroke
|
RECRUITMENT, STROKE
|
Flow diagram of patient recruitment.The interaction effect between time and therapy in NIHSS, FMA-UE, BI, and ARAT. The Y-axis represents mean values with error bars. The X-axis represents time points pre, post, and after 90 days.The changes in the outcome measures over time for NIHSS, BI, FMA-UE and ARAT in the Cerebrolysin group. **** The changes in outcome measures over time for NIHSS, BI, FMA-UE, and ARAT in the Placebo group. The solid circles represent the outliers (without effect). **** The comparisons in time points between groups in NIHSS, BI, FMA-UE and ARAT. **** Descriptive statistics of basic characteristics.Legend: MMSE—The Mini-Mental State Examination, NIHSS—National Institute of Health Stroke Scale, BI—Barthel Index, FMA-UE—the Fugl-Meyer assessment score for upper limb, ARAT—The Action Research Arm Test, The changes in the outcome measures over time.Legend: NIHSS—National Institute of Health Stroke Scale, BI—Barthel Index, FMA-UE—the Fugl-Meyer assessment score for upper limb, ARAT—The Action Research Arm Test, F—test statistics for two-way repeated measures analysis of variance or robust two-way repeated measures analysis of variance, The changes in the outcome measures over time for NIHSS, BI, FMA-UE and ARAT for the Cerebrolysin group.Legend: NIHSS—National Institute of Health Stroke Scale, BI—Barthel Index, FMA-UE—the Fugl-Meyer assessment score for upper limb, ARAT—The Action Research Arm Test, The changes in outcome measures over time for NIHSS, BI, FMA-UE, and ARAT in the placebo group.Legend: NIHSS—National Institute of Health Stroke Scale, BI—Barthel Index, FMA-UE—the Fugl-Meyer assessment score for upper limb, ARAT—The Action Research Arm Test, Changes in outcomes over time in the Cerebrolysin group and Placebo group.Legend: NIHSS—National Institute of Health Stroke Scale, BI—Barthel Index, FMA-UE—the Fugl-Meyer assessment score for upper limb, ARAT—The Action Research Arm Test, Mean ± Standard Deviation.The comparisons in outcomes between groups.Legend: NIHSS—National Institute of Health Stroke Scale, BI—Barthel Index, FMA-UE—the Fugl-Meyer assessment score for upper limb, ARAT—The Action Research Arm Test,
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PMC9958781
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Background
|
hypertension
|
HYPERTENSION
|
Nighttime blood pressure (BP) and an abnormal nocturnal BP dipping profile are important cardiovascular risk factors in patients with hypertension. This post hoc analysis investigated the effects of sacubitril/valsartan on 24‐hour BP in patients with mild‐to‐moderate hypertension and in patient subgroups based on nocturnal BP dipping status.
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PMC10227270
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Methods and Results
|
−7.3, hypertension, 24‐hour
|
HYPERTENSION
|
Data from a randomized clinical trial comparing the BP‐lowering effects of 8 weeks of treatment with sacubitril/valsartan (200 or 400 mg/d) and olmesartan (20 mg/d) in Japanese patients with mild‐to‐moderate hypertension were analyzed. The primary end point was change in 24‐hour, daytime, and nighttime BP in patient subgroups based on nocturnal BP dipping status (dipper, nondipper). Six hundred thirty‐two patients with baseline and follow‐up ambulatory BP data were included. Both sacubitril/valsartan dosages reduced 24‐hour, daytime, and nighttime systolic BP, and 24‐hour and daytime diastolic BP, to a significantly greater extent than olmesartan in the dipper and nondipper groups. However, between‐group differences in nighttime systolic BP were more significant in the nondipper group (difference [95% CI] for sacubitril/valsartan 200 and 400 mg/d versus olmesartan 20 mg/d: –4.6 [95% CI, −7.3 to −1.8] and −6.8 [95% CI, −9.5 to −4.1] mm Hg, respectively;
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PMC10227270
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Conclusions
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HYPERTENSION
|
This analysis highlights the value of sacubitril/valsartan therapy in patients with a nondipper profile of nocturnal BP and confirms this agent's potent 24‐hour BP‐lowering effect in Japanese populations with hypertension.
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PMC10227270
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Registration
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URL:
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PMC10227270
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Subject Categories
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Supplemental Material is available at For Sources of Funding and Disclosures, see page 10.
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PMC10227270
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Nonstandard Abbreviations and Acronyms
|
diastolic blood pressuresystolic blood pressure
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PMC10227270
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Clinical Perspective
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PMC10227270
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What Is New?
|
Nondipper
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These are the first data on the differential 24‐hour blood pressure (BP)‐lowering effects of sacubitril/valsartan in patient subgroups based on the nocturnal BP dipping profile.Nondipper patients showed the most significant decreases in ambulatory BP (especially nighttime BP) during sacubitril/valsartan versus olmesartan treatment.
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PMC10227270
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What Are the Clinical Implications?
|
hypertension, cardiovascular disease
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EVENTS, HYPERTENSION, CARDIOVASCULAR DISEASE, BLIND
|
Given the contribution of nighttime BP and an abnormal nocturnal BP dipper pattern to cardiovascular risk, treatment with sacubitril/valsartan impacts multiple mechanisms that could improve cardiovascular outcomes in patients with hypertension.A substantial body of evidence shows that nocturnal hypertension is a significant risk factor for developing cardiovascular disease and the occurrence of cardiovascular disease events.Despite this, management of nocturnal hypertension remains an unmet medical need, because most current antihypertensive medication is given once daily in the morning. Unfortunately, this leaves a therapeutic blind spot in the early morning hours, where drug levels (and BP‐lowering effects) are at their lowest point before morning drug dosing. One approach to overcoming these issues is bedtime dosing of antihypertensive therapy.One of these newer agents is the angiotensin receptor neprilysin inhibitor sacubitril/valsartan, which has recently been approved in Japan to treat hypertension.Therefore, this post hoc analysis of randomized clinical trial data evaluated the antihypertensive effects of sacubitril/valsartan compared with olmesartan on 24‐hour, daytime, and nighttime ambulatory BP in patients with mild‐to‐moderate hypertension and in patient subgroups (phenotypes) based on nocturnal BP dipping status.
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PMC10227270
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METHODS
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PMC10227270
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Study Design
|
ESSENTIAL HYPERTENSION
|
The data that support the findings of this study are available from Novartis AG upon reasonable request.This post hoc analysis used data from a multicenter, randomized, double‐blind, parallel‐group study comparing the BP‐lowering effects of sacubitril/valsartan and olmesartan in Japanese patients with mild‐to‐moderate essential hypertension (NCT01599104), conducted from June 2012 to April 2013.
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PMC10227270
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Study Participants
|
Nondipper
|
Full details of patient inclusion and exclusion criteria have been reported previously.Dipper: mean nighttime (10 Nondipper: mean nighttime ambulatory BP fall of <10% versus daytime ambulatory BP
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PMC10227270
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Study Procedures and Treatments
|
There was a 2‐ to 4‐week single‐blind, placebo run‐in period at baseline. The run‐in period for previously treated patients was 3 to 4 weeks, during which all existing antihypertensive therapy was tapered and discontinued, and the run‐in period for previously untreated patients was 2 weeks. After the run‐in period, patients meeting the entry criteria were randomized in a 1:1:1 ratio to 8 weeks' treatment with sacubitril/valsartan 200 mg/d, sacubitril/valsartan 400 mg/d, or olmesartan 20 mg/d, taken once daily in the morning.
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PMC10227270
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Clinical End Points
|
The primary end point for this analysis was the change in 24‐hour, daytime, and nighttime BP from baseline to 8 weeks in patient subgroups based on nocturnal BP dipping status (dipper and nondipper). Secondary end points included the following: change from baseline to 8 weeks in 24‐hour BP; change from baseline to 8 weeks in levels of NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide); changes from baseline to 8 weeks in 24‐hour, daytime, and nighttime BP in patient subgroups based on baseline characteristics; rates of BP control at 8 weeks, where BP control was defined as 24‐hour SBP <130 mm Hg and 24‐hour diastolic BP (DBP) <80 mm Hg; safety in patient subgroups based on nocturnal BP dipping status; and between‐group differences in change from baseline to 8 weeks in the daytime and nighttime SBP.
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PMC10227270
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Follow‐Up and Assessments
|
Ambulatory BP measurement over 24 hours was conducted at 2 time points in a subset of participants in the original study. The first 24‐hour ambulatory BP measurement was performed after a patient had qualified for randomization based on office BP measurement but before administering the first dose of double‐blind study medication. The second ambulatory BP measurement was performed at week 8. Patients who withdrew from the study before week 8 did not need to have ambulatory BP measurements performed. At each 24‐hour ambulatory BP assessment period, the measurement device was attached to the nondominant arm, and both BP and heart rate were measured at study‐specified intervals. Readings were downloaded from device memory and then analyzed by a central laboratory.
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PMC10227270
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Statistical Analysis
|
SECONDARY
|
The analysis population included patients with ambulatory BP data at baseline and all follow‐up visits. Demographics and baseline characteristics are presented using descriptive statistics, including mean±standard deviation, minimum, first quartile, median, third quartile, and maximum values for continuous variables, and frequencies and percentages for categorical variables. Between‐group differences were determined using an independent ANCOVA was used to assess treatment effects on changes from baseline to 8 weeks in 24‐hour ambulatory BP in patient subgroups based on nocturnal BP dipping status. A repeated measures ANCOVA model with treatment, postdosing hours (time elapsed since drug administration), and treatment by postdosing hour interaction as fixed‐effect factors, and mean 24‐hour ambulatory SBP/DBP at baseline and 8 weeks as repeated measures was used. In addition, between‐group differences in mean change in 24‐hour ambulatory BP from baseline to 8 weeks with 95% CIs were determined.Statistical analysis for secondary end points included 1‐way ANOVA, ANCOVA, least‐squares means with 95% CIs, and paired Statistical analyses were performed using SAS version 9.4 or higher. A 2‐sided
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PMC10227270
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RESULTS
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PMC10227270
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|||
Study Population
|
HYPERTENSION
|
Of the full analysis set from the randomized trial (n=1161), 632 patients (54% in total, 56% treated with sacubitril/valsartan 200 and 400 mg/d and 51% treated with olmesartan) had ambulatory BP data at baseline and follow‐up and were included in this analysis (Patient Demographics and Clinical Characteristics at Baseline, Overall, and by Treatment GroupValues are the number of patients (%) or mean±standard deviation. ACE indicates angiotensin‐converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; BP, blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; PP, pulse pressure; and SBP, systolic blood pressure.Data are available from 403 patients.Three patients (1 in each treatment group) had treatment‐naïve hypertension.
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PMC10227270
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Overall Change in Ambulatory
|
Changes in 24‐hour, daytime, and nighttime ambulatory SBP and DBP from baseline to week 8 were more significant with both dosages of sacubitril/valsartan compared with olmesartan (Figure
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PMC10227270
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Change in ambulatory systolic blood pressure (A) and diastolic blood pressure (B) from baseline to week 8.
|
Data are least‐squares mean change±standard error (repeated measures ANCOVA model). Daytime: 6
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PMC10227270
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Change in Ambulatory
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Significant reductions in 24‐hour, daytime, and nighttime SBP and DBP from baseline to week 8 were seen during treatment with sacubitril/valsartan 200 and 400 mg/d and olmesartan 20 mg/d in both the dipper and nondipper groups (Figure
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PMC10227270
|
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