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Data availability | The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request. | PMC10141830 |
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Declarations | PMC10141830 |
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Conflict of interest | The authors declare that they have no conflict of interest. | PMC10141830 |
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Ethical approval | The study has been approved by our institutional review board (IRB:21/2022) and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. | PMC10141830 |
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References | PMC10141830 |
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Abstract | PMC10225203 |
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Aim | gastric cancer, breast cancer | GASTRIC CANCER, BREAST CANCER | Pyrotinib (an irreversible pan‐ErbB small‐molecular tyrosine kinase inhibitor) was approved in human epidermal growth factor receptor 2 (HER2)‐positive breast cancer and showed great antitumor activity in preclinical studies of gastric cancer (GC). This study was first designed to prospectively assess pyrotinib in pretreated HER2‐positive GC. | PMC10225203 |
Methods | This multicenter, phase I study followed a standard “3 + 3” design and included two parts. In the pyrotinib part, pyrotinib was administered orally, once per day at dose levels of 240, 320, 400, and 480 mg. In the pyrotinib plus docetaxel part, patients received pyrotinib (qd, d1‐21, q3W) combined with docetaxel (60 mg/m | PMC10225203 |
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Results | A total of 25 patients were enrolled and received pyrotinib ( | PMC10225203 |
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Conclusions | toxicities | Pyrotinib alone and combined with docetaxel showed acceptable toxicities in patients with pretreated HER2‐positive GC. | PMC10225203 |
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Trial Registration | This study was registered with This phase 1 study demonstrate the safety and efficacy of pyrotinib in HER2 positive GC. Pyrotinib alone and plus docetaxel are well‐tolerated and show anti‐tumor activity. But combination with docetaxel cannot improve the efficacy.
Dan Liu, Furong Kou, and Jifang Gong contributed equally. | PMC10225203 |
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BACKGROUND | gastric cancer (GC).Pyrotinib, tumor, breast cancer | PROLIFERATION, TUMOR, BREAST CANCER | Human epidermal growth factor receptor 2 (HER2) was a key therapeutic target in gastric cancer (GC).Pyrotinib was a novel oral, irreversible pan‐ErbB small‐molecular TKI blocking HER1, HER2, and HER4, which was approved in HER2‐positive breast cancer (BC). And it has been reported that pyrotinib could inhibit the proliferation of gastric cells overexpressing HER2 (NCI‐N87 and BT474 cell line) in vitro.Docetaxel, a broad‐spectrum phase M cycle‐specific cytotoxic drug which promotes the polymerization of tubules into stable microtubules, inhibits their polymerization and significantly reduces the tumor proliferation.Hereby, we first performed a multicenter, phase I study to prospectively assess the safety and pharmacokinetic (PK) characteristics of pyrotinib alone or plus docetaxel in refractory HER2‐positive GC patients, and explore the preliminary antitumor activity as well. | PMC10225203 |
PATIENTS AND METHODS | PMC10225203 |
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Patient eligibility | cancers, autoimmune diseases, hemorrhage, syphilis, chronic disease or, effusion, gastrointestinal obstruction, hypokalemia | HEPATITIS B, CANCERS, VIRUS, HEART DISEASE, BRAIN METASTASES, AUTOIMMUNE DISEASES, HYPOMAGNESEMIA, HUMAN IMMUNODEFICIENCY VIRUS INFECTION, HEMORRHAGE, MALIGNANCIES, SYPHILIS, HEPATITIS C, EFFUSION, ONCOLOGY, GASTROINTESTINAL OBSTRUCTION | Patients with pathologically confirmed advanced HER2‐positive (3+ or 2+ staining intensity by immunohistochemistry or gene amplification by fluorescence in situ hybridization amplification [HER2:CEP17 ratio ≥2]) GC who suffered previous standard treatments (without docetaxel or other anti‐HER2 TKIs) failure or intolerance were considered. Other key inclusion criteria were age 18–70 years, measurable lesions per RECIST V1.1, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate organ and bone marrow function, and a life expectancy of at least 3 months.Patients were excluded if they had a history of autoimmune diseases or requirement of long‐term use of steroids (≥50 days); brain metastases; symptomatic or uncontrolled third space effusion; unable to take the drugs orally; uncontrolled hypokalemia and hypomagnesemia; a history of other antitumor therapy within 4 weeks before or during study; active hemorrhage within 2 months before study; chronic disease or gastrointestinal obstruction effecting absorption; other malignancies (except for cured locally cancers) within 5 years before study entry; a history of active hepatitis B virus, hepatitis C virus, syphilis or human immunodeficiency virus infection; uncontrolled heart disease. Each patient provided written informed consent. | PMC10225203 |
Study design and treatment | This multicenter, open‐label, phase I dose escalation study was conducted in China from September 2014 (ClinicalTrials. gov, NCT02378389). The study was approved by the ethics committee of each study center and performed in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and Declaration of Helsinki.The phase I study was composed of two parts: dose escalation of pyrotinib monotherapy and in combination with docetaxel. This study followed a standard “3+3” design (Figure Study design. | PMC10225203 |
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Endpoints | SECONDARY | The primary endpoints were to assess the maximum tolerated dose (MTD), safety and the recommended phase II dose (RP2D) of pyrotinib monotherapy and pyrotinib in combination with docetaxel. The secondary endpoints included PK evaluation and preliminary efficacy of pyrotinib monotherapy and pyrotinib combined with docetaxel. | PMC10225203 |
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Safety assessment | nausea, DLTs, neutropenia, fever, fatigue, diarrhea, thrombocytopenia, vomiting, anemia, heart and renal insufficiency | NEUTROPENIA, ADVERSE EVENTS, THROMBOCYTOPENIA, ANEMIA, BLEEDING TENDENCY | Safety was evaluated throughout the study. All adverse events (AEs) were recorded, the severity was assessed according to NCI‐CTCAE (V.4.0), and the relationship with pyrotinib or docetaxel was judged.DLT criteria included Grade 4 neutropenia with a duration of ≥7 days, Grade 3 or 4 neutropenia with fever, Grade 3 thrombocytopenia with bleeding tendency or Grade 4 thrombocytopenia, Grade 3 or 4 anemia; ≥ Grade 2 heart and renal insufficiency, Grade 3 or 4 non‐hematologic AE (except for Grade 3 fatigue lasting ≤3 days, recoverable diarrhea, nausea, and vomiting after supportive care). DLTs were assessed in 21 days following the first dose. | PMC10225203 |
The main PK parameters were estimated by a standard noncompartmental method using Phoenix WinNonLin (Pharsight, version 6.3, Pharsight Corp.), including elimination half‐life (In pyrotinib monotherapy part, blood samples were obtained on D1 and D21 of the first cycle at predose; 1, 2, 3, 4, 5, 6, 8, 12, and 24 h after the first dose; and on C1D8 and C1D15 at predose. In pyrotinib in combination with docetaxel part, the samples were obtained on D1 of the first cycle at predose; 5 min, 30 min, 1, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 h after the first dose; and on C1D8 and C1D15 at predose. Samples were also collected on Day 21 of the first cycle at predose and 1, 2, 3, 4, 5, 6, 8, 12, and 24 h after the first dose. The whole blood was centrifuged (3500 rpm at 4°C for 10 min) and obtained plasma samples were stored at −80°C until analysis. | PMC10225203 |
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Efficacy assessment | death, Tumor | DISEASE PROGRESSION, TUMOR | Tumor responses were evaluated based on RECIST 1.1 at screening and every two cycles until disease progression or the start of new antitumor treatment. The complete and partial response would be confirmed after 4 weeks. All the progression‐free survival (PFS) was defined as the time from the start of the first dose to disease progression or death of any cause. The overall survival was defined as the time from the start of the first dose to death. Survival status was obtained from medical records and followed up by telephone. | PMC10225203 |
Statistical analysis | tumor | TUMOR | Statistical analysis was performed by SPSS Version 22.0 (SPSS Inc.). The safety was assessed in patients who received at least one dose of study drugs. Patient characteristics and efficacy were assessed in the full analysis set, including patients who received at least one dose of study drugs. Descriptive statistics were used to assess demographic characteristics, safety, and tumor response outcomes. The Kaplan–Meier method was used for time‐to‐event endpoints. | PMC10225203 |
RESULTS | PMC10225203 |
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Patient characteristics | Between September 2014 and February 2017, 25 patients with HER2‐positive GC were finally enrolled in this study. The median age was 58 years (range 39–65). And the majority of patients (Patient demographics and baseline characteristics.
Other anti‐HER2 therapies: trastuzumab emtansine (T‐DM1), pertuzumab.All the patients ( | PMC10225203 |
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Safety | ADVERSE EVENTS | A total of 25 patients were included in safety analysis (Table Treatment‐related adverse events of all grades in pyrotinib monotherapy part.
Treatment‐related adverse events of all grades in pyrotinib combined with docetaxel part.In the combination with docetaxel part, for no DLT observation of pyrotinib alone at dose level of 240 mg and occurrence of effective case ( | PMC10225203 |
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PK | Totally, 22 patients provided plasma samples for PK analysis (monotherapy, Mean plasma concentration of pyrotinib following (A) single and (B) multiple doses in the monotherapy part (PK population). | PMC10225203 |
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Antitumor activity | PD, SD, diarrhea | DISEASE PROGRESSION, DISEASE, BEST | In all, from September 2014 to February 2017, 24 patients finished efficacy assessment (monotherapy, Best overall response in evaluable population in monotherapy part and combination therapy part.Abbreviations: CR, complete response; DCR, disease control rate: (CR + PR + SD) %; ORR, overall response rate: (CR + PR) %; PD, progressive disease; PR, partial response; SD, stable disease.Six patients were enrolled in the 400 mg dose cohort. One patient was not evaluable. This patient received one cycle treatment and experienced Grade 3 diarrhea, which was defined as DLT. Finally, this patient dropped out of the study.This patient achieved PR after two cycles of treatment, but had PD after four cycles of treatment. So, the confirmed efficacy was SD. Cut‐off date: February 28, 2017.Waterfall plot of best objective response of all enrolled patients. Maximum reduction in target lesions from baseline for patients in the 240–480 mg dose cohorts in (A) the monotherapy part and (B) the combination therapy part. The best response for target lesions per patient was determined on the basis of RECIST 1.1 criteria. Dashed lines at −30 and 20 indicate RECIST 1.1 criteria for partial response and progressive disease, respectively. In the pyrotinib monotherapy part, the overall objective response rate (ORR) was 21% and the disease control rate (DCR) was 43%, with three patients achieving PR, three patients achieving stable disease, eight patients suffering progressive disease. The patients achieving PR were distributed in dose levels of 240, 400, and 480 mg. None of the patients achieving PR received prior anti‐HER2 regimens. The PFS ranged from 2.67 to 20.47 months. Of note, at the time of data cut‐off (February 28, 2017), one patient with PFS of 20.47 months was at the 400 mg dose level and was still ongoing with pyrotinib. Based on the safety data, PK analysis in this study and the results of phase I study in BC,In the pyrotinib combined with docetaxel part, there were two patients achieving PR, five patients experiencing SD, with the ORR and DCR of 20% and 70%, respectively. At the dose level of 400 mg, although only one patient suffered DLT, three of four patients experienced quick disease progression. Hence, the enrollment of this dose level was stopped early for poor efficacy. Based on the data of safety, PK, and efficacy, the RP2D of pyrotinib was 400 mg. | PMC10225203 |
DISCUSSION | toxicity, diarrhea | DISEASE | Pyrotinib is an irreversible pan‐ErbB small‐molecular TKI, which has been approved in HER2‐positive BC. While the safety and efficacy data were limited in HER2‐positive GC, only several small‐sample retrospective studies and case reports involved it.In the monotherapy part, diarrhea was the most common TRAE. And two patients (13%) experienced Grade 3 diarrhea in the 400 mg dose cohort, one of which was defined as DLT. In the phase I study in HER2‐positive BC, pyrotinib monotherapy was generally well tolerated at doses up to 480 mg.Pyrotinib exposure was dose‐dependent with a nonlinear relationship versus dose, which was different from the PK profile data reported in the metastatic BC population. Besides, limited data suggested coadministration with docetaxel had no apparent effect on the PK of pyrotinib.The ORR of pyrotinib alone and pyrotinib combined with docetaxel was 21% and 20%, which was relatively unsatisfied in patients with pretreated HER2‐positive GC. Unlike BC, pyrotinib alone could not show encouraged efficacy in HER2‐positive GC. But there were indeed some patients who achieved long‐lasting disease control time for more than 12 months. So, pyrotinib might be effective in some selected patients. This similar result was also shown in studies of other anti‐HER2 TKIs, including lapatinib, afatinib, and neranib.The main limitations of this study are typical of early‐phase clinical studies. Most clinical cohorts had a small size and required further investigations. The lack of a control arm makes it difficult to accurately confirm the effect of combination with docetaxel. But based on the early signs demonstrated in this study, the combination with docetaxel increased the toxicity, rather than the efficacy, which might suggest us to try other combination strategy. Furthermore, the resistance mechanism of pyrotinib had been explored in cell lines and patient‐derived xenograft models. Dysregulation of the CCND1‐CDK4/6‐Rb pathway was found to be to the main cause of pyrotinib resistance in preclinical AVATAR mouse. | PMC10225203 |
CONCLUSIONS | HER2 POSITIVE GASTRIC CANCER | In brief, pyrotinib alone and combined with docetaxel had shown acceptable safety profile in HER2 positive gastric cancer. Pyrotinib plus docetaxel might not further improve the efficacy. | PMC10225203 |
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AUTHOR CONTRIBUTIONS | PMC10225203 |
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FUNDING INFORMATION | This phase I clinical trial (NCT02378389) was sponsored by Jiangsu Hengrui Medicine Co., Ltd., and supported by the National Natural Science Foundation of China (no. 91959205). | PMC10225203 |
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CONFLICT OF INTEREST STATEMENT | Jianjun Zou and Xiaoyu Zhu are employees of Hengrui. All other authors declare no competing interests. | PMC10225203 |
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ETHICS STATEMENT | Cancer | CANCER | This study was approved by the ethics committee of Beijing Cancer Hospital (2014YW17) and Sun Yat‐sen University Cancer Center (A2014‐029‐02). | PMC10225203 |
Supporting information |
Click here for additional data file. | PMC10225203 |
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ACKNOWLEDGMENTS | We are grateful to all patients and their families and thank the investigators and the research staff of this study. | PMC10225203 |
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DATA AVAILABILITY STATEMENT | data‐access | Reasonable request for data sharing should be submitted to the corresponding author after the indication has been approved in China. The sponsor will review the proposal and consider to share the data providing the requestor signs a data‐access agreement. | PMC10225203 |
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REFERENCES | PMC10225203 |
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INTRODUCTION | DISEASE, CORTEX | UP165, a standardized Current Centers for Disease Control and PreventionWhile there are some psychotropic clinical and anecdotal data available to support the usage of sedative and anxiolytic plants like kava kava, Cortisol, a glucocorticoid released from the adrenal cortex, is more than a stress hormone known to regulate multiple vital metabolic and physiological functions in the body through the hypothalamic-pituitary-adrenal (HPA) axis. Sleep is among several physiologic functions regulated by HPA axis,In a similar study, compared with healthy young subjects (average of 21 years old), healthy older adults (average of 71 years old) were found to sleep more poorly at night, as indicated by increased wake time and decreased percentage of slow-wave sleep. Similarly, interaction between altered HPA-axis functions and disturbed sleep was underlined by studies indicating a positive correlation between total wake time and 24-hour urinary cortisol secretionPreviously, the mood-enhancing effect of UP165, a These clinically meaningful desired outcomes were postulated partially as a result of the mechanisms of action of UP165 such as (1) structural similarity of the active in UP165 to that of melatonin and the production of a melatonin-like effect, (2) increased endogenous biosynthesis of serotonin and melatonin through induction of rate-limiting enzymes, such as tryptophan-5-hydroxylase, and | PMC9889011 |
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MATERIALS AND METHODS | PMC9889011 |
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Receptor binding assay | To test the ability of UP165 to bind to the melatonin binding site of the melatonin receptor 1 (MT1) and 2 (MT2) melatonin receptors, membrane-bound human MT1 and MT2 melatonin receptors were incubated with UP165 in the presence of [Cell membranes from human recombinant Chinese hamster ovary (CHO)-K1 cells expressing the human melatonin MT1 receptor were harvested and incubated with UP165 at concentrations 0.78, 1.56, 3.12, 6.25, 12.5, 25, 50, 100, 200, and 400 | PMC9889011 |
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Clinical study design | This study enrolled 45 healthy volunteers (24 female and 21 male subjects) to participate in a 6-week sleep and overall well-being trial. Subjects were randomized to receive UP165 (Supplement) or a nonactive corn starch placebo (Placebo). Subjects (age range 19–73 years) were instructed to consume the supplement or placebo ∼60 minutes before bedtime daily for 4 weeks after a 2-week baseline period (no supplementation). The active test material, UP165, was administered orally at 250 and 500 mg/day. Following a 2-week baseline monitoring period, groups were assigned. Sleep Quality (latency, efficiency, and deep/rapid eye movement [REM] time) was monitored nightly, and POMS and Pittsburgh Sleep Quality Survey were monitored weekly for each subject in each group for a period of 4 weeks. Salivary cortisol level was also determined for all subjects on Day 0 and weekly for 4 weeks. | PMC9889011 |
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Study measuring tools | (1) Objective sleep quality was measured using the Garmin VivosmartThe sum of scores for these seven components yields one global score, with higher scores corresponding to worsening sleep quality and efficiency. | PMC9889011 |
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Inclusion criteria | Healthy adults, able to provide informed consent, and with the ability/desire to participate in a 4-week supplementation regimen and sleep quality study were included in the study. | PMC9889011 |
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Exclusion criteria | sleep disorders | Inability to complete prescribed supplement regimen, current use of incompatible medications or supplements, high use of caffeine (500 mg/day) or other stimulants, off shift and night shift workers, and those diagnosed with severe sleep disorders were excluded from this study. | PMC9889011 |
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Ethics and regulatory approval | MAY | The study was performed in compliance with the requirements of Good Clinical Practice/International Council for Harmonisation (GCP/ICH) Guidelines for clinical trials. The Study gained full board review from Institutional Review Board (IRB) on May 14, 2020, by WCG Aspire IRB. Protocol number Maizinol (UP165) 2020 IRB Tracking number 20201258. | PMC9889011 |
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Participant informed consent | All subjects provided written informed consent to participate in the study before being screened and a copy was provided for their information. Subjects were also free to withdraw from the study at any time without giving a reason. | PMC9889011 |
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Compliance | ADVERSE EVENT | Adverse event (AE) data were collected by subject reporting of any AE, which were captured in subject charts. This study was conducted in a healthy population, and subjects were contacted weekly by phone call, text, or email. Subjects were given a number to call if there was any issue to report. Compliance was a combination of wearing the device to capture data, staying away from consumption of excluded supplements that could interfere with test materials activity, and adhering to scheduled daily supplement consumption, which was verified through pill count to ensure the investigational product was taken as per protocol. This was done during the weekly contact with the participants. | PMC9889011 |
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Statistical analysis | Data were analyzed using John's Macintosh Project (JMP) 14.0 data analysis software (SAS Institute, Cary, NC, USA). The results are represented as mean ± standard deviation. Statistical significance between groups was calculated by means of single-factor analysis of variance (ANOVA) followed by a paired | PMC9889011 |
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RESULTS | PMC9889011 |
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Receptor binding assay result | OVARY | UP165 (Lot. No. FP041019-01) was tested in duplicate at 10 concentrations for its MT1 and MT2 binding affinity. UP165 showed a fourfold increase in MT2 receptor binding affinity. UP165 had a dose-responsive curve with an ICPercent inhibition of ligand binding to MT1. Human recombinant CHO-K1 cells expressing the human melatonin MT1 receptor were incubated with UP165 at 10 concentrations and run in duplicate. The percent inhibition for the test compound was calculated compared to a 1% DMSO vehicle control. CHO, Chinese Hamster Ovary; DMSO, dimethylsulfoxide; MT1, melatonin receptor 1.Percent inhibition of ligand binding to MT1. Human recombinant CHO-K1 cells expressing the human melatonin MT2 receptor were incubated with UP165 at 10 concentrations and run in duplicate. The percent inhibition for the test compound was calculated compared to a 1% DMSO vehicle control. MT2, melatonin receptor 2. | PMC9889011 |
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Clinical study compliance and completion rate | Participants were compliant for all the procedures and supplementation for the duration of the study. Forty-two (23 female and 19 male) participants completed the study. No AE was reported for test article or placebo. Three participants dropped out of study due to scheduling conflicts (Study Enrollment and DropoutThe study enrolled 45 volunteers to participate in a 6-week trial. | PMC9889011 |
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Effect of UP165 on deep sleep | Increase in the deep sleep time was observed for participants who were supplemented with the test article, UP165. Compared to placebo, these increases in the deep sleep time were statistically significant for participants supplemented with the 250 mg/day UP165 at week 2 and 3 with Effect of UP165 on the Average Deep Sleep Values on Healthy ParticipantsThe study enrolled 45 volunteers to participate in a 6-week trial. Participants (age range 19–73) consumed the supplement or placebo ∼60 minutes before bedtime daily for 4 weeks after a 2-week baseline period (no supplementation). Data in parenthesis are SD, standard deviation.When the percent of increase from the baseline was computed, ranges of 30.5–45.6% and 27.9–47.4% increase in deep sleep time were observed for those participants supplemented with 250 and 500 mg/day UP165, respectively (Percent baseline change of UP165 on deep sleep of healthy participants. The study enrolled 45 volunteers to participate in a 6-week trial. Participants (age range 19–73) consumed the supplement or placebo ∼60 minutes before bedtime daily for 4 weeks after a 2-week baseline period (no supplementation). The active test material UP165 was administered orally at 250 and 500 mg/day. * | PMC9889011 |
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Effect of UP165 on total sleep time | SE | Compared to the baseline, UP165 resulted in a moderate, but statistically significant (The average total sleep time before and after three supplements. The study enrolled 45 volunteers to participate in a 6-week trial. Participants (age range 19–73) consumed the supplement or placebo ∼60 minutes before bedtime daily for 4 weeks after a 2-week baseline period (no supplementation). The active test material UP165 was administered orally at 250 and 500 mg/day. Data represented as mean ± SE. * | PMC9889011 |
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Effect of UP165 supplementation on sleep quality improvement as it was measured by PSQI | SE | The PSQI is a self-rated questionnaire that assesses sleep quality and disturbances over a 4-week time interval. Participants who were supplemented with UP165 showed a statistically significant improvement in self-rated questionnaires, indicating the effect of UP165 in enhancing sleep quality and efficiency in healthy participants. UP165 supplementation produced significantly improved sleep quality as early as week 1 (PSQI global scores for three supplement groups. The study enrolled 45 volunteers to participate in a 6-week trial. Participants (age range 19–73) consumed the supplement or placebo ∼60 minutes before bedtime daily for 4 weeks after a 2-week baseline period (no supplementation). The active test material UP165 was administered orally at 250 and 500 mg/day. Data represented as mean ± SE. *Effect of UP165 Supplementation on Sleep Quality Improvement as Measured by Pittsburgh Sleep Quality IndexThe study enrolled 45 volunteers to participate in a 6-week trial. Participants (age range 19–73) consumed the supplement or placebo ∼60 minutes before bedtime daily for 4 weeks after a 2-week baseline period (no supplementation).ANOVA, analysis of variance; PSQI, Pittsburgh Sleep Quality Index.The placebo effect (31.6% increase in PSQI from baseline) observed in week 1 for the placebo group was nonexistent for the remainder of the study period ( | PMC9889011 |
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Effect of UP165 on salivary cortisol level | CORTEX | Cortisol, one of the major glucocorticoid hormones secreted by the adrenal cortex, is among the hormones that regulate human sleep, with its increase being associated with poor sleep quality. In this clinical study, subjects supplemented with UP165 showed a progressive decrease in salivary cortisol level through the course of the study (Percentage changes of salivary cortisol levels from supplements of three test articles. The study enrolled 45 volunteers to participate in a 6-week trial. Participants (age range 19–73) consumed the supplement or placebo ∼60 minutes before bedtime daily for 4 weeks after a 2-week baseline period (no supplementation). The active test material UP165 was administered orally at 250 and 500 mg/day. *Effect of UP165 on Salivary Cortisol LevelThe study enrolled 45 volunteers to participate in a 6-week trial. Participants (age range 19–73) consumed the supplement or placebo ∼60 minutes before bedtime daily for 4 weeks after a 2-week baseline period (no supplementation). Data in parenthesis are Interestingly, as shown in Reductions of cortisol level such as 11.0%, 21.8%, 20.2%, and 27.5% for the 250 mg/day and 15.0%, 18.2%, 29.5%, and 36.3% for the 500 mg/day UP165 were observed for weeks 1–4, respectively. In contrast, 6.2%, 9.8%, 1.7%, and 3.4% increase in the salivary cortisol level was observed for the placebo group for the same time frame. These cortisol findings align well with the deep sleep findings described above, affirming the improved sleep quality and efficiency experienced as a result of UP165 supplementation. | PMC9889011 |
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Effect of UP165 on POMS | The POMS is a well-validated psychological rating scale used to assess both overall well-being (Global Mood State) and distinct specific mood states (Subscales). Data were analyzed to determine the presupplementation and postsupplementation effects of the test article, UP165, on the overall well-being of test subjects (Global mood state measurements from three test articles. The study enrolled 45 volunteers to participate in a 6-week trial. Participants (age range 19–73) consumed the supplement or placebo ∼60 minutes before bedtime daily for 4 weeks after a 2-week baseline period (no supplementation). The active test material UP165 was administered orally at 250 and 500 mg/day. **The psychological mood state profile of subjects was also assessed for each subject in the supplementation groups for each dimension of mood state. As seen in Profile of Mood States Improvements from BaselineThe study enrolled 45 volunteers to participate in a 6-week trial. Participants (age range 19–73) consumed the supplement or placebo ∼60 minutes before bedtime daily for 4 weeks after a 2-week baseline period (no supplementation). Data in parenthesis are POMS, Profile of Mood States. | PMC9889011 |
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DISCUSSION | hypothermia, daytime sleepiness, dizziness, morning grogginess, headache | MUSCLE RELAXATION | Despite significant research efforts for sleep and mental health management, to date, available intervention options from natural sources are very limited. In particular, the sleep aid market is significantly saturated by high doses of synthetic melatonin or cocktails of melatonin and other botanical extracts with minimal to no clinical evidence to support their meaningful clinical usage. Higher dosages of synthetic melatonin supplements could also produce side effects such as morning grogginess, daytime sleepiness, headache, dizziness, and hypothermia.Supplementation of a standardized corn leaf extract, UP165, improved sleep quality of clinical study participants by increasing the deep sleep stage of sleep approximately by half an hour. The total deep sleep times at the start of the study period for the 250 mg/day, 500 mg/day, and placebo were 64, 68, and 58 minutes, respectively, indicating neither the supplement nor the placebo group was to the level considered good-quality sleep per night. Following the 4-week supplementation, the deep sleep times were found to be increased to 92, 94, and 62 minutes for the 250 mg/day, 500 mg/day, and placebo group, respectively. Such increase of deep sleep time for high-dose Maizinol group was statistically significant at week 2 and 4 with Due to small number of subjects in each group of this pilot study, both low- and high-dose Maizinol group showed statistically strong trend of increased deep sleep time with The increase in the deep sleep time observed in the UP165-supplemented group was possibly a direct reflection of the fourfold higher affinity of UP165 to the MT2 receptor, which is known to induce deep sleep when activated. The improved sleep quality findings from the sleep tracker were also verified by the PSQI questionnaire with participants showing a 10-fold increase in quality and efficiency of sleep improvement as a result of 250 mg/day of UP165, compared to that of participants who were supplemented with the placebo.Again, substantiating the objective measures from the individual sleep tracker, when participants were asked about their mental health status using the POMS questionnaire, they provided statistically significant improvements in mood state and well-being compared to their baseline (37–58% improvement at 250 mg/day and 36–42% improvement at 500 mg/day), whereas the improvements for the placebo group were very minimal (9–15% improvement) and statistically nonsignificant.The clinical superiority in performance observed for the UP165-supplemented participants compared to the placebo was closely correlated to the level of salivary cortisol during the course of the study. It has been known that high cortisol level is strongly linked to premature nocturnal awakening, decrease in deep sleep, and hence poor sleep quality.It has been well documented that sleep displays a close and inverse relationship with increased level of cortisol and HPA axis regulation.These clinical study results support the fact that participants who were supplemented with a standardized corn leaf extract, UP165, had significantly reduced cortisol levels (up to 36%) and increased slow-wave deep sleep time (up to 30 minutes), which translated to better sleep quality when compared to the placebo group. These clinical findings also added additional dimension to the mechanism of action of UP165, in that, by reducing cortisol level, there is a possibility that UP165 could correct a dysregulated HPA axis, leading to normal homeostasis of vital physiological functions, including sleep. This clinical evidence in association with the ability of UP165 to induce the body to synthesize endogenous melatonin, directly binding to MT1 and MT2 receptors, being structurally similar to melatonin, and having a muscle relaxation property, could produce a potential additive and/or synergistic effect that will lead to enhanced induction and maintenance of sleep.Collectively, UP165 showed a statistically significant (1) dose-correlated reduction in salivary cortisol level compared to placebo; (2) improved deep sleep time in a dose-correlated manner; (3) increased total sleep time compared to baseline; (4) improved sleep quality and efficiency as measured by PSQI; and (5) improved overall well-being as measured by POMS scale. Therefore, UP165 could be used as a safe nutritional supplement for a 24-hour support for a better quality and efficiency of sleep at night and for improved mood state and overall well-being by day. These data suggest the possibility of the standardized, natural, hormone-free, corn leaf extract, UP165, to be considered a natural alternative to a synthetic melatonin. | PMC9889011 |
ACKNOWLEDGMENT | The authors would like to express their best gratitude to Dr. Teresa Horm, who oversaw the receptor binding assay, and participated in data calculation and interpretation; Dr. Ping Jiao, who conducted activity-guided structure elucidations and identification; Dr. Wenwen Ma; Dr. Qi Jia; Mr. Regan Miles; and Unigen's team for their invaluable support for the completion of this clinical study. | PMC9889011 |
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AUTHOR DISCLOSURE STATEMENT | Both authors, except S.M.T. and J.A.T. are current Unigen employees; therefore, they have competing financial interests. | PMC9889011 |
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FUNDING INFORMATION | The clinical study was fully sponsored by Unigen. The authors would like to extend their utmost gratitude to Mr. Bill Lee, the owner of Econet/Unigen, Inc., who supported the entire project described in this article. | PMC9889011 |
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REFERENCES | PMC9889011 |
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Background | Children’s conduct and emotional problems increased during the COVID-19 pandemic. | PMC10415938 |
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Objective | We tested whether a smartphone parenting support app, | PMC10415938 |
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Methods | Supporting Parents And Kids Through Lockdown Experiences (SPARKLE), a randomized controlled trial, was embedded in the UK-wide COVID-19: Supporting Parents, Adolescents and Children during Epidemics (Co-SPACE) longitudinal study on families’ mental health during the pandemic. Parents of children aged 4 to 10 years were randomized 1:1 to | PMC10415938 |
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Results | A total of 320 participants were randomized to | PMC10415938 |
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Trial Registration | ClinicalTrials.gov NCT04786080; https://clinicaltrials.gov/ct2/show/NCT04786080 | PMC10415938 |
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Introduction | PMC10415938 |
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Background | SAID | UK COVID-19 mitigation strategies (eg, extended joint confinement, social isolation, and homeschooling) presented families with unprecedented challenges [Providing parents with advice and support can reduce children’s conduct and emotional problems [The focus for each booster and the parenting challenge it was designed to address were originally selected from a larger library of parent training program content [We further sought information about parenting support needs through a short anonymous questionnaire completed by parents and carers (eg, grandparents). Responses to the questionnaire identified four key features that should be included in the app: (1) downloadable text resources, (2) videos with parenting tips, (3) expert advice and information on how to apply this advice, and (4) experiences shared by other parents. We also conducted 2 web-based focus groups with parents of young children to better understand their views on how support needs could be addressed by the app. These groups indicated that the app should help parents understand why their children behave in a certain way. It should also provide reassurance that all parents struggle at some point when raising a child and many face similar parenting challenges. Parents have asked for tools to help them deal with difficult behaviors and provide a demonstration of how to use these tools in practice. As a parent said, “apps are all about...well...application.” Focus group discussions indicated that content should be snappy and engaging and provided in lay language and by people parents can relate to. Finally, the app should be accessible (eg, videos should have captions) and use visual tools (eg, cartoons and props) to explain any difficult concepts.As a result of this co-design work with parents, the The | PMC10415938 |
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Objectives | In Supporting Parents And Kids Through Lockdown Experiences (SPARKLE), using a randomized controlled trial (RCT) comparison of | PMC10415938 |
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Methods | PMC10415938 |
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Patient and Public Involvement | Parents of young children were involved in all aspects of the study, including designing the research, designing the app, participating in the Trial Steering Committee (TSC), and interpreting the results. The SPARKLE Patient and Public Involvement parent panel included 13 members, with 1 parent member who sat on the TSC. The parent panel tested the app before use within SPARKLE and provided electronic feedback on the app and the data collected from the app. We also included parents outside the panel to specifically inform the | PMC10415938 |
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Study Design | SPARKLE was a rapid-deployment 2-arm superiority parallel group RCT of | PMC10415938 |
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Participants | RECRUITMENT | Participants were parents or carers of children aged 4 to 10 years. The inclusion criterion for Co-SPACE was parents aged ≥18 years residing in the United Kingdom with a child aged 4 to 16 years. For SPARKLE, only families with children aged 4 to 10 years and access to a compatible smartphone were included. Recruitment took place on the web via email newsletters; parent networks, support organizations, and charities; schools; children’s services departments; and media announcements. Parents of children aged 4 to 10 years who were already in Co-SPACE when SPARKLE started were invited to take part, whereas others could join Co-SPACE and SPARKLE after the trial started. Parents provided separate written informed consent for Co-SPACE and SPARKLE. | PMC10415938 |
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Randomization and Blinding | Participants were allocated to the study arm in a 1:1 ratio by simple randomization automatically at baseline through the | PMC10415938 |
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Ethics Approval | Ethics approval was granted by King’s College London (reference HR-20/21-21,451) and the University of Oxford (references R73153/RE001 for SPARKLE and R69060/RE001 for Co-SPACE). | PMC10415938 |
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Procedures | PMC10415938 |
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Interventions | PMC10415938 |
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Parent Positive | The | PMC10415938 |
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FAU Arm | Parents allocated to FAU received access to | PMC10415938 |
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Data Collection | Measures were administered at baseline (T1) and at1 (T2) and 2 (T3) months after randomization through Qualtrics as part of Co-SPACE data collection. | PMC10415938 |
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Outcomes | PMC10415938 |
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Clinical Outcomes | SECONDARY | The primary outcome was parent-reported child conduct problems using the conduct subscale of the Parent-reported SDQ conduct problems score at 2 months after randomization (T3) was a secondary outcome. Other validated secondary outcomes were T2 and T3 measures of (1) parent-reported child emotional problems measured on the SDQ 5-item emotional symptoms subscale and (2) parental psychological distress measured on the | PMC10415938 |
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Health Economic Measures | Retrospective child-related use of health and social care services, including those provided in schools, was measured at T2 and T3 using a modified version of the | PMC10415938 |
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Intervention Use and Satisfaction | The main | PMC10415938 |
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Other Measures | ADVERSE EVENT, EVENTS | Family characteristics and demographic information were collected at baseline. Data on lockdown-related circumstances (eg, being in lockdown) were collected. Adverse events (AEs) were measured using a questionnaire developed for SPARKLE that asked parents to report negative events related to their child’s and their own physical and mental health problems and their relationships or daily activities. The information was coded to categorize the type, severity, seriousness, and relatedness. | PMC10415938 |
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Sample Size Calculation | The target sample size of 616 provided 90% power to detect a Cohen | PMC10415938 |
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Analysis | The | PMC10415938 |
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Outcome Analysis | All analyses were carried out using Stata (version 17.0; StataCorp). Baseline and postrandomization app use variables were described by intervention arm and overall, with categorical variables described using frequencies and proportions and continuous variables described using mean and SD or median and IQR as appropriate. App usage between T1 to T2 and T1 to T3 was reported, instead of T1 to T2 and T2 to T3 as specified in the SAP. Differences between arms were assessed using mixed-effects linear models (LMMs) analysis of covariance models, with T2 and T3 measures as dependent variables and a random intercept at the participant level. All models included age, gender (both prespecified), T1 outcomes, intervention arm, time, intervention arm by time interaction, and any additional baseline variables found to be predictive of missingness as fixed effects. Marginal mean Missing outcome data were summarized; those with at least 1 postrandomization value were included in the LMM models under the intention-to-treat principle. Baseline variables that predicted (at Medical (physical and psychological) and nonmedical familial AEs (eg, reduction in school attendance) and serious AEs were summarized. | PMC10415938 |
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Economic Analysis | Between-arm differences in costs and QALYs were analyzed using generalized linear models with bootstrapped 95% CIs adjusted for prespecified T1 covariates and CHU9D scores. Adjustment for differences in T1 costs was not possible as service use data were not collected in Co-SPACE; the CA-SUS was administered at T2 and T3 only. The primary economic analysis was a cost-utility analysis at T2. Costs were calculated from the National Health Service and personal social services perspective. Effects were measured in terms of QALYs. Incremental cost-effectiveness ratios were calculated, and nonparametric bootstrapping was used to propagate sampling uncertainty surrounding the mean incremental cost-effectiveness ratios by generating 1000 estimates of incremental costs and QALYs [ | PMC10415938 |
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Oversight of the Trial | The independent TSC, consisting of clinicians, statisticians, health economists, policy makers, and Patient and Public Involvement representatives, met every 4 months. No interim analyses were undertaken. The role of the Data Monitoring and Ethics Committee was taken over by the TSC. | PMC10415938 |
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Results | PMC10415938 |
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Recruitment and Retention | MAY | Between May 19, 2021, and July 26, 2021, a total of 646 parents were recruited, of whom 320 (49.5%) were assigned to CONSORT (Consolidated Standards of Reporting Trials) diagram. No longer providing=no Co-SPACE follow-up data. Exclusions: a member of staff signed up to test the randomization system. Early in the study, 2 individuals accessed the platform from 2 different devices on 2 different occasions each with the same email address, completed the baseline surveys, and were randomized. Procedures were then put in place to rectify this, and only the first set of baseline data and randomized allocation were used. Co-SPACE: COVID-19: Supporting Parents, Adolescents and Children during Epidemics; FAU: follow-up as usual. | PMC10415938 |
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Service Use, Costs, and Economic Outcomes | Service use and cost data are presented in Tables S5-S7 in Excluding influential outliers, complete case mean costs were lower in the | PMC10415938 |
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Economic Analysis | SECONDARY | The results of the primary, sensitivity, and secondary economic analyses are summarized in Table S9 in | PMC10415938 |
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Discussion | PMC10415938 |
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Limitations | The RCT was conducted during spring 2021 and summer 2021, when pandemic-related restrictions were beginning to ease (ie, children were not homeschooled en masse, and restrictions on social contacts had relaxed). In this sense, we are unable to generalize our findings to more restrictive lockdown periods or to nonrestricted contexts, and parents of children in Co-SPACE reported a drop in conduct problems when restrictions eased [ | PMC10415938 |
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Conclusions | ARC, Maudsley, anxiety | POSITIVE | This was the first RCT of a parenting support app designed specifically to support parents in the general population during the COVID-19 pandemic and one of the few examples of a trial within a cohort in our field. It used a rigorous design in a large sample and collected data on a range of outcomes over a 2-month period. The SPARKLE trial was funded by the Economic and Social Research Council: Grant ES/V016393/1 from the, UK. Co-SPACE was funded by grants from UKRI (2004CQ002/BS3) and the Westminster Foundation. The animations used in the Parenting Boosters were produced through funding by The Maudsley Charity and the South London and Maudsley NHS Foundation Trust. KG and ESBs contributions represent, respectively, independent research part funded by the National Institute for Health and Care Research (NIHR) Applied Maudsley Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and the NIHR Applied Research Collaboration South London (NIHR ARC South London) at King’s College Hospital NHS Foundation Trust. CC receives funding from the NIHR Applied Research Collaboration Oxford and Thames Valley at Oxford Health NHS Foundation Trust. PW receives funding through a NIHR Development and Skills Enhancement award. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.We are grateful to all the families who were involved in the study. Thanks also go to the parents involved in our parent advisory panels and the SPARKLE Trial Steering Committee who provided guidance and advice throughout the study. We would like to thank other members of the Co-SPACE study team for their assistance with data collection: Adrienne Shum, Amy McCall, Dr Samantha Pearcey, Dr Jasmine Raw and Dr Simona Skripkauskaite. We would like to acknowledge parent moderators (Brigid Bose, Samira Elzaki, Sarah Inkpen, Emelia Kuagbela, Camille Le Boulba and Jessica Miranda) who facilitated the parent-to-parent support as part of the Parent Exchange. Thanks also go to Jo Nicoll and Claire Groarke from the Empowering Parents, Empowering Communities Team at the Centre for Parent and Child Support for providing clinical guidance to the parent moderators. We would also like to thank our experts who gave up their time to answer questions submitted by our SPARKLE parent participants (Chloe Chessell, Professor Cathy Creswell, Professor Crispin Day, Dr Rafael González, Professor Alice Gregory, Dr Victoria Hallett, Professor Katherine Mansell, Dr Melernie Meheux, Dr Lauren Peile, Professor Paul Ramchandani, Professor Stephen Scott, Professor Emily Simonoff, Professor Edmund Sonuga-Barke, Dr Gauri Verma, Dr Matthew Woolger and Jezima Zahir). We are thankful to our design partner TOAD for their work in producing Parent Positive in such a short time frame, in particular Henry Waterfall-Allen, and the well-known UK television and film personalities who, as parents, narrated the animations (Olivia Colman, Sharon Horgan, Danny Dyer, Rob Brydon, Jessica Ennis-Hill, Holly Willoughby, Romesh Ranganathan and Shappi Khorsandi).Conflicts of Interest: CC receives royalties from the sale of books for parents and clinicians on managing child anxiety problems from LittleBrown and Guilford Press. CD is the lead developer and has a nonfinancial interest in a number of parenting programs including Empowering Parents Empowering Communities, Helping Families Programme, Family Partnership Model, and BabyCHAT. EJSSB was involved in the development of the New Forest Parent Programme, Families Under Pressure and Parent Positive. Receiving royalties for a book on the former. PW receives royalties from the sale of books for parents on helping their children overcome common psychological and emotional problems from LittleBrown. All other authors declare no conflicts of interest.Outcome analysis using complier average causal effect, economic analysis, and CONSORT (Consolidated Standards of Reporting Trials) checklist.CONSORT-EHEALTH (V 1.6.1) checklist. | PMC10415938 |
Abbreviations | Anxiety | adverse eventChild and Adolescent Service Use ScheduleChild Health Utility–9 DimensionsConsolidated Standards of Reporting TrialsCOVID-19: Supporting Parents, Adolescents and Children during EpidemicsDepression, Anxiety, and Stress ScaleEmpowering Parents Empowering Communitiesfollow-up as usuallinear mixed modelquality-adjusted life yearrandomized controlled trialStatistical Analysis PlanStrengths and Difficulties QuestionnaireSupporting Parents And Kids Through Lockdown ExperiencesStructured E-Parenting Support appbefore randomization1 month after randomization2 months after randomizationTrial Steering Committee | PMC10415938 |
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Subject terms | TRD, nausea, somnolence, treatment-resistant depression, depressive disorder, dizziness, treatment-resistant, headache, depression, Depression | ADVERSE EVENTS, REMISSION, NASOPHARYNGITIS | Patients with treatment-resistant depression (TRD) have higher rates of relapse and pronounced decreases in daily functioning and health-related quality of life compared to patients with major depressive disorder who are not treatment-resistant, underscoring the need for treatment choices with sustained efficacy and long-term tolerability. Adults with TRD who participated in ≥1 of 6 phase 3 “parent” studies could continue esketamine treatment, combined with an oral antidepressant, by enrolling in phase 3, open-label, long-term extension study, SUSTAIN-3. Based on their status at parent-study end, eligible participants entered a 4-week induction phase followed by an optimization/maintenance phase, or directly entered the optimization/maintenance phase of SUSTAIN-3. Intranasal esketamine dosing was flexible, twice-weekly during induction and individualized to depression severity during optimization/maintenance. At the interim data cutoff (01 December 2020), 1148 participants were enrolled, 458 at induction and 690 at optimization/maintenance. Mean (median) cumulative duration of maintenance esketamine treatment was 31.5 (37.7) months (totaling 2769 cumulative patient-years). Common treatment-emergent adverse events (≥20%) were headache, dizziness, nausea, dissociation, somnolence, and nasopharyngitis. Mean Montgomery–Åsberg Depression Rating Scale (MADRS) total score decreased during induction, and this reduction persisted during optimization/maintenance (mean [SD] change from the baseline to the endpoint of each phase: induction −12.8 [9.73]; optimization/maintenance +1.1 [9.93]), with 35.6% and 46.1% of participants in remission (MADRS total score ≤12) at induction and optimization/maintenance endpoints, respectively. Improvement in depression ratings generally persisted among participants who remained in maintenance treatment, and no new safety signal was identified during long-term treatment (up to 4.5 years) using intermittent-dosed esketamine in conjunction with daily antidepressant. | PMC10267177 |
Introduction | depressive disorder, TRD, MDD, treatment-resistant depression | Approximately one-third of patients with major depressive disorder (MDD) do not achieve an antidepressant response despite treatment with multiple antidepressants and are considered to have treatment-resistant depression (TRD) [Esketamine nasal spray (Spravato | PMC10267177 |
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Methods | PMC10267177 |
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Ethical practices | An Institutional Review Board (United States) or Independent Ethics Committee (all other locations) approved the study protocol and its amendments. The study is being conducted in accordance with ethical principles of the Declaration of Helsinki, Good Clinical Practices (GCP), and applicable regulatory requirements. Written consent was obtained from all participants prior to enrollment. | PMC10267177 |
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