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Discussion | anhedonia, TSD, depressive symptoms, MDD, depression | TSD | This was the first study to investigate the safety and pharmacokinetics of the CNS penetrant and selective P2X7 receptor antagonist JNJ-54175446 in MDD, and to explore its potential effects on mood-related phenomena such as reward propensity and changes in peripheral cytokine production following TSD. Although healthy subjects had received single doses of JNJ-54175446 up to 600 mg [TSD was applied as a behavioral challenge to investigate whether its effects on mood and mood-related symptoms could be modulated by JNJ-54175446. TSD alleviated depressive symptoms on both self-reported and clinician rated rating instruments, which lasted until the last study day (day 10). Although this again confirms TSD as an adequate behavioral challenge paradigm to induce a rapid recovery from depressive symptoms, it conflicts with pre-existing literature reporting transient mood improvement that disappears after a single post-TSD night of recovery sleep [JNJ-54175446 demonstrated no effect on depressive symptoms when administered prior to TSD, suggesting that JNJ-54175446 does not produce rapidly-acting antidepressant effects. Furthermore, no significant effects of JNJ-54175446 were observed on mood improvement, which in all groups occurred after TSD and subsequently did not substantially change during the remainder of the study. However, the reduction in anhedonia observed (SHAPS) in the placebo group after recovery sleep was significantly attenuated by JNJ-54175446 in both the early (day 1) and late (day 4) starting groups. Since JNJ-54175446 was administered for the first time in the delayed group as a loading dose during the TSD procedure on the morning before the recovery sleep, this effect on hedonic capacity appeared to occur acutely, suggesting a stabilizing effect of JNJ-54175446 even after a single high dose on the anhedonia levels, such that they persisted during TSD. A similar pattern, although not statistically significant, was suggested by the total points lost on the PILT assessment of reward learning. This apparent mood stabilizing effect, which nevertheless blunted the beneficial effects of TSD on anhedonia, contrasts with the effects of P2X7R antagonism on stress-induced anhedonia seen in animal experiments, [Overall, there were no differences in levels of IL-1β in peripheral blood in response to JNJ-57417446 treatment as compared to placebo, which may reflect the multiple paths for releasing IL-1β that do not involve P2X7 receptors. However, JNJ-57417446 did decrease ex-vivo IL-1β release by LPS-stimulated peripheral white blood cells in the presence of the P2X7 receptor agonist BzATP. This provided proof of pharmacological activity in the blood, which considering the high blood-brain-barrier permeability of JNJ-57417446 is also likely to have occurred in the CNS.Several limitations were identified in this study. We observed a protracted effect of TSD on depression severity ratings in MDD patients and, as a consequence, could not determine a clear difference between and the placebo group and patients receiving a loading dose of JNJ-54175446 prior to the TSD recovery night. Although previous investigations suggested that combining TSD with bright light therapy is effective in sustaining its antidepressant effect [In conclusion, JNJ-54175446 was safe and well tolerated by MDD patients. In line with its pharmacological properties, JNJ-54175446 reduced IL-1β release from LPS-stimulated peripheral white blood cells in the presence of the P2X7R agonist BzATP. TSD (combined with light therapy) alleviated depressive symptoms on both self-reported and clinician rated rating instruments, which lasted until the end of the observation period (day 10). This is longer than previously reported in the literature, which may have prevented evaluation of any potential antidepressant effect of post-TSD administration of JNJ-54175446. However, the current study suggested that JNJ-54175446 at the relatively high exposures tested may blunt the reduction of anhedonia that occurs in MDD patients after TSD. These potential mood stabilizing effects on hedonic capacity warrant further exploration in future studies of the P2X7 antagonist mechanism. | PMC10363543 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41398-023-02557-5. | PMC10363543 | ||
Acknowledgements | MB acknowledges support from the NIHR Oxford cognitive health Biomedical Research Centre and Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. | PMC10363543 | ||
Author contributions | The author contributions to the paper are as follows: study conception and design: KR, PdeB, PvdA, JMAvG, GEJ; data collection: KR, JMAvG, GEJ; analysis and interpretation of results and draft paper preparation: KR, PdB, PvdA, JMAvG, MC, LvN, WCD, AB, MB, GEJ. All authors reviewed the results and approved the final version of the paper. | PMC10363543 | ||
Competing interests | The current study was funded by Janssen Research and Development. KR MD, Dr GJ and Prof Dr JvG declare no competing interests. Dr PdB, Dr PvdA, Dr HB, Dr MC, Dr AB, Dr LvN and Prof Dr WD are employees of Janssen and own Johnson and Johnson equity. Dr MB is employed by the University of Oxford and has acted as a consultant for Jansen Research and CHDR. | PMC10363543 | ||
References | PMC10363543 | |||
Trial objective | stroke | STROKE | To verify whether conventional rehabilitation combined with specific virtual reality is more effective than conventional therapy alone in restoring hand motor function and muscle tone after stroke. | PMC10071242 |
Trial design | This prospective single-blind randomized controlled trial compared conventional rehabilitation based on physiotherapy and occupational therapy (control group) with the combination of conventional rehabilitation and specific virtual reality technology (experimental group). Participants were allocated to these groups in a ratio of 1:1. The conventional rehabilitation therapists were blinded to the study, but neither the participants nor the therapist who applied the virtual reality–based therapy could be blinded to the intervention. | PMC10071242 | ||
Participants | Forty-six patients (43 of whom completed the intervention period and follow-up evaluation) were recruited from the Neurology and Rehabilitation units of the Hospital General Universitario of Talavera de la Reina, Spain. | PMC10071242 | ||
Intervention | Each participant completed 15 treatment sessions lasting 150 min/session; the sessions took place five consecutive days/week over the course of three weeks. The experimental group received conventional upper-limb strength and motor training (100 min/session) combined with specific virtual reality technology devices (50 min/session); the control group received only conventional training (150 min/session). | PMC10071242 | ||
Results | As measured by the Ashworth Scale, a decrease in wrist muscle tone was observed in both groups (control and experimental), with a notably larger decrease in the experimental group (baseline mean/postintervention mean: 1.22/0.39; difference between baseline and follow-up: 0.78; 95% confidence interval: 0.38–1.18; effect size = 0.206). Fugl-Meyer Assessment scores were observed to increase in both groups, with a notably larger increase in the experimental group (total motor function: effect size = 0.300; mean: − 35.5; 95% confidence interval: − 38.9 to − 32.0; wrist: effect size = 0.290; mean: − 5.6; 95% confidence interval: − 6.4 to − 4.8; hand: effect size = 0.299; mean: − -8.9; 95% confidence interval: − 10.1 to − 7.6). On the Action Research Arm Test, the experimental group quadrupled its score after the combined intervention (effect size = 0.321; mean: − 32.8; 95% confidence interval: − 40.1 to − 25.5). | PMC10071242 | ||
Keywords | PMC10071242 | |||
Introduction | Stroke, stroke, hand motor function, upper-limb deficits, poststroke | STROKE, PATHOLOGY, CEREBROVASCULAR ACCIDENT, STROKE | Stroke is a leading cause of long-lasting disability. As many as 41.5 million new cases occur yearly in Europe, and 3.7 million survivors experience long-lasting impairments, whereas less than 15% of patients achieve full poststroke recovery [It is estimated that 80% of stroke patients have upper-limb deficits and have decreased activity and use of the paretic hand in daily life [Most of the functional recovery after diagnosis occurs in the first three months, although neural repair processes and behavioral improvements continue to show slight plasticity in later phases of the rehabilitation process [Rehabilitative treatment of the upper limb is recognized by consensus among survivors, caregivers and health professionals as one of the top ten research priorities for poststroke recovery [During poststroke hand treatment, special attention must be paid to restoring the different biomechanical movements and curvature of the hand in order to provide a stable base and correct alignment as a prerequisite for dexterity training and modulation of reaching movements [Various therapies based on a conventional approach have been demonstrated to be useful, achieving good results in terms of hand rehabilitation: motor imagery training seems to improve the precision and accuracy of movement, as well as the reception of sensory signals, by fostering activation of dormant synapses and accelerating reperfusion of the ischemic penumbra [Another important aspect of hand-focused therapy programs is the use of a generous dose of intense repetition [Recent years have witnessed an increased use of technology-based and especially virtual reality–based neurorehabilitation approaches, which have allowed the creation of effective simulated environments and provided multimodal, controllable and customizable stimulation [There are two major types of virtual reality-based systems used in neurorehabilitation: nonspecific virtual reality (N-SVR) systems and specific virtual reality (SVR) systems. These two classes differ in that systems of the former type use game consoles and video games designed by the entertainment industry. Such consoles (Wii, Xbox, PlayStation, etc.) run games that are not designed for adults suffering from a neurological pathology and do not allow monitoring of movement or other motor or functional variables of the affected body segments. Thus, N-SVR systems are not designed for the neurophysiological recovery of the brain, and they do not focus on the neuronal connections necessary for the recovery of hand function after stroke. In contrast, SVR systems are specifically designed to promote motor learning and recovery, optimizing the acquisition, retention and generalization of motor skills. SVR systems incorporate key features of virtual reality and add objective, quantitative movement monitoring and exergames to facilitate the motor recovery of the hand (regular voluntary movement, arches of hand curvature, grasping, pinch grips and gross manipulation). In addition, SVR systems comply with the principles of neurorehabilitation: mass practice (repetitive training), high dosing (intensive training), structured practice, task-specific practice (ADL-relevant skills training), variable practice, multisensory stimulation (training in which the feedback is not limited to the visual modality), increasing difficulty (individualized training), explicit feedback (training that provides knowledge about the results), implicit feedback (training that provides task-relevant implicit signals), avatar representation (immersive training) and encouragement of the use of the paretic limb (training that counteracts compensation) [In this sense, neurorehabilitation SVR systems allow rehabilitation work to proceed in a functional way and with specific intervention objectives, and these systems can easily evaluate and document progress during sessions [In this regard, Laver et al. [Choosing the appropriate neurorehabilitation strategies to maximize clinical results in stroke patients takes priority. In this sense, a combination of more traditional neurophysiological approaches and motion-based therapies, delivered at a high intensity and in a large dose in motivating game-related environments where motion can be made, offers an important advantage in restoring the motor function of the upper limb [Our clinical trial differs from the studies included in the review as follows: (1) it adds SVR technology (HandTutorIkbali and collaborators [The Kinect sensor, independent of any specific software for rehabilitation after stroke, is able to capture gross movement of the upper limb, but it cannot identify hand motion and does not include exergames designed for hand motor rehabilitation.Programs incorporating SVR technology to train distal motor function after cerebrovascular accident remain little known [It was hypothesized that, compared to control group (CG) participants, adults randomized to the experimental group (EG) would achieve an increased degree of hand motor function improvement and have superior results on the Fugl-Meyer Assessment, Ashworth Scale, and Action Research Arm Test. | PMC10071242 |
Methods | PMC10071242 | |||
Study design, randomization, and blinding | This was a prospective single-blind randomized controlled trial comparing conventional rehabilitation (CG) with the combination of conventional rehabilitation and an SVR system (EG); all reporting of this trial is in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement [The study was approved by the Research and Medical Ethics Committee of the Integrated [healthcare] Area of Talavera de la Reina (protocol code: 12/2018), and it complies with the Declaration of Helsinki. All participants received verbal and written information about the study and gave their written informed consent.The participants were randomly assigned in a 1:1 ratio to the CG or the EG by a researcher who did not participate in the intervention or the evaluation process. The clinical practitioners who applied the conventional intervention and those who administered the baseline, postintervention, and follow-up clinical assessments to the intervention groups (CG and EG) were blinded. The participants and the researcher who applied VRBT could not be blinded. | PMC10071242 | ||
Participants | end-stage cancer, Stroke, cognitive impairment, trembling, stroke, function loss, upper-limb motor impairment, psychiatric, dysmetria, hemineglect | STROKE, PATHOLOGY, STROKE | The study included 46 patients (43 of whom completed the intervention period and follow-up evaluation), with a mean age of 63.1 years (SD: 12.8). Nineteen percent (n = 8) were women. The participants were recruited from the Neurology and Rehabilitation units of the Hospital General Universitario of Talavera de la Reina, and none of them suffered from moderate or severe cognitive impairment that prevented them from following verbal and visual instructions from the therapist or the SVR technology. All participants had been diagnosed with stroke and met the following inclusion criteria: (1) age between 18 and 85 years; (2) maximum time of six months since diagnosis; (3) upper-limb motor impairment (Fugl-Meyer Assessment, Ashworth Scale and ARAT); (4) dependency in ADLs (Stroke Impact Scale; version 3.0); (5) life expectancy greater than 6 months (no diagnosis of any life-threatening condition such as end-stage cancer); and (6) absence of any other serious and disabling pathology.According to baseline tests for determining motor function loss in the upper limb after stroke, we included patients who showed (1) scarce or no reflex activity, (2) absence or limitation of voluntary movements in flexion and extension synergies, (3) limitations in shoulder flexion–extension and adduction-abduction and wrist flexion–extension and stabilization, (4) difficulty grasping and gripping with the most affected hand, and (5) trembling or dysmetria (Fugl-Meyer Assessment). Furthermore, most of the patients selected for the study (especially those who had been diagnosed more than 20 days prior) showed a slight or a substantial increase in their muscle tone (Ashworth Scale) and difficulties in pinching, gripping or handling objects and making larger-scale movements, for example, placing their hand behind their head (Action Research Arm Test). We never set minimum or maximum scores for the testing tools applied; instead, we focused on movement limitations and elements that might affect the individual’s functional independence after stroke.Four exclusion criteria were defined: presence of another neurological diagnosis, severe hemineglect, psychiatric pathology, and signed revocation of informed consent [ | PMC10071242 |
Outcomes | In our study, we used the basic set of assessment measures recommended for clinical practice and research to assess the physical function and activity level of the upper limb; these measures are included in the current standardized protocols of evidence-based practice [The primary outcome was hand motor function. For quantification purposes, we applied the Fugl-Meyer Assessment-Upper Extremity (FMA-UE), the ARAT and the Ashworth Scale (a muscle tone evaluation).Upper limb motor function (FMA-UE and ARAT) and muscle tone (Ashworth Scale) were evaluated and recorded before the treatment began (baseline), three weeks later (postintervention) and three months after its completion (follow-up). | PMC10071242 | ||
Fugl-Meyer assessment-upper extremity (FMA-UE) | stroke | STROKE | The FMA is considered a valid, fully suitable instrument to evaluate the motor function of the upper limb after stroke, given its excellent psychometric properties and its appropriate scale. The upper-limb subscale of this instrument, the FMA-UE, is of great value for predicting the degree of independence that can be achieved one year after stroke. The FMA-UE is composed of 113 items, and each item on the evaluation scale is scored as an ordinal variable ranging from 0 to 2 points [ | PMC10071242 |
Action research arm test (ARAT) | The ARAT assesses the ability to manipulate small and large objects, with a variety of qualitative items that allow a numerical quantification of each of the subtests: grasp, grip, pinch and gross movement [ | PMC10071242 | ||
Ashworth Scale | The Ashworth Scale measures resistance to passive movement on a scale of 0 to 4; it has a Kendall’s W of 0.765 (p = 0.000) for the elbow, and its reliability is 0.4 to 0.75 for 95% of the assessments [ | PMC10071242 | ||
Data analysis | poststroke | REGRESSION, LITTLE | The sample size was calculated using the program Epidat 4.2. At the time when the study was designed, the methodologist and statistician calculated the size of the sample using an estimated effectiveness ratio of 90% in the experimental group and 50% in the control group, a power level of 80%, and confidence level of 95% (p < 0.05). The minimum necessary sample size was calculated to be 20 participants per group. Then, we decided to increase the sample size by 15% to compensate for potential losses (during field work and in the course of the study). The small sample size in each group could have led to a change in the variance in the case of missing data imputation, which would have compromised the accuracy of the final data.Once we had gathered all the data, we carried out an analysis of missing values with SPSS; we observed a value below 5%, which can be attributed to chance. The estimated effectiveness in both groups (90% and 50%) was determined after considering the outcomes from studies already published on conventional poststroke motor rehabilitation, VRBT and the two approaches combined [Student's t tests and Chi-squared tests were performed to compare the clinical and sociodemographic variables of the intervention groups. Differences in the Ashworth, ARAT, and FMA-UE scores at baseline, postintervention, and 3-month follow-up were analyzed with inter- and intragroup ANOVAs and Student's t tests. Statistical significance was defined by a p value of less than 0.05.In this study of experimental intervention with the HandTutorThe analysis of missing data from the CG was carried out with multiple imputation in the analysis (expectation maximization and regression method), with a Little’s Chi-squared statistic of 36.280 (degrees of freedom = 28; p = 0.136).The assignment of participants to the intervention groups was random and unknown to the researcher performing the statistical analysis. | PMC10071242 |
Results | PMC10071242 | |||
Discussion | spasticity, stroke, hand motor function, poststroke, subacute stroke | STROKE, DISEASE | The main purpose of this clinical trial was to test whether conventional rehabilitation combined with SVR technology is more effective than an intervention based exclusively on occupational therapy and physiotherapy for improving hand motor function in adults with subacute stroke.Previous studies [In this study of patients with a poststroke interval of less than 6 months (EG mean: 55.3 days at baseline), patients randomly allocated to the EG followed a motor training protocol with SVR technology designed for improving hand motor function; interventions were delivered over the course of three weeks, five consecutive days a week, with each session lasting 50 min. In addition, patients in this group a received 100-min session of conventional treatment (occupational therapy and physiotherapy) along with each SVR training session. This combined treatment regimen yielded promising functional results regarding distal motor control of the upper limb, as resistance to movement decreased (spasticity), while the functionality and motion of the hand and wrist increased. In light of the functional results, it is important to highlight that the HandTutorThe introduction of SVR systems into conventional rehabilitation processes offers new models of simulation that provide participants with the experience of motivating, stimulating, realistic environments, allowing safe practice of techniques based on meaningful, entertaining daily tasks [Ikbali et al., in their intervention, chose the Kinect sensor in combination with the commercial console Xbox 360 by MicrosoftThe results of this study suggest that VRBT using MeditouchThe differences in Ashworth Scale scores for the wrist found in our study coincide with the results published by Young-Bin et al. [Our study revealed positive results in terms of hand function after the combination of SVR and conventional physiotherapy and occupational therapy. The difference between baseline and follow-up measurements reflected functional improvements after the experimental intervention: 5.6 points on the wrist scale of the FMA-UE, 8.9 points on the hand scale of the same instrument (p = 0.000 for each), and 32.8 points on the ARAT. In this respect, it is important to note the proximity of the three-week postintervention differences to the minimum detectable change on the Spanish version of the FMA-UE, which corresponds to 7.3 points six weeks after intervention. The effect size of the intervention (hIncreased practice results in greater ability as long as the exercises are challenging, progressive and skill-based [A noteworthy feature that likely contributes to the utility of the HandTutorFor our study, we designed a daily intervention plan, devoting 50 min per session to motor training with SVR technology devices.High-quality upper-limb training focusing on the motion quality of the injured segment is difficult to achieve in the time allowed in standard rehabilitation programs, in which patients are encouraged to carry out tasks through compensation [Similar results have been found in studies that combined conventional techniques with the use of robotics [The use of VRBT in treatments aimed at functional recovery of the upper limb in stroke patients brings about an enriched, interactive environment that positively influences neuroplasticity, especially in the subacute phase of the disease, in which the level of brain reorganization is at a maximum [The above results suggest that SVR-facilitated exercise-based intervention programs benefit the recovery of hand motor function in people with stroke.Recent studies on stroke patients observed significant changes and great improvements in ARAT and FMA-UE results when patients received upper-limb therapy 5 days a week over 3 , 6 and 12 weeks; the declared intention in those studies was to make motion practice as realistic as possible, with increasing progress in joint movement culminating in full practice of the actual physical task [The SVR technology devices used for our study focused on the joints and body segments damaged by stroke, differentiating and isolating the movements and the active range of joint motion if necessary. The HandTutorEvidence from this study reveals that virtual reality has the potential to create effective environments for rehabilitation with safe, multimodal, individualized simulations while providing feedback and options regarding repetition, intensity, and training in specific tasks; these features are not common among conventional physical therapies but are useful for promoting the recovery of upper limbs after stroke [ | PMC10071242 |
Limitations of the study | poststroke | The results of the present study cannot be extrapolated to other poststroke phases or to rehabilitation programs with fewer weekly sessions.The design of our study does not include a long-term follow-up to clarify the evolution of the intervention groups (CG vs. EG) or the differences found. In addition, this study was limited to a single center, in contrast to several studies with multicenter randomized controlled designs [ | PMC10071242 | |
Conclusions | stroke, spasticity | STROKE | The outcomes of the study suggest that conventional rehabilitation combined with an SVR-based method can be more effective than conventional therapy alone in improving hand motor function and voluntary movement and normalizing muscle tone in subacute stroke patients. With combined treatment, hand and wrist functionality and motion increased; resistance to movement (spasticity) decreased, and this decrease was sustained over time.Patients showed significant clinical improvements in the fine motor skills and functionality of the affected hand, with a large effect size, and these gains were achieved in less time than if conventional rehabilitation alone were used. | PMC10071242 |
Acknowledgements | The authors would like to thank the participants and the staff of the Hospital General Universitario (Talavera de la Reina, Spain) for their collaboration in this study. | PMC10071242 | ||
Author contributions | MRH: conceptualization, methodology, software, validation, formal analysis, investigation, and writing—original draft preparation. BPL: conceptualization, validation, and writing—original draft preparation. JJCA: conceptualization, methodology, software, validation, formal analysis, and writing—original draft preparation. AICS, JLMC and AMM: writing—review and editing and supervision. All authors read and approved the final manuscript. | PMC10071242 | ||
Funding | The study was sponsored by the University of Castilla-La Mancha (grant #2020-GRIN-29192). This funding contributed to the purchase of the SVR technology used for this study. | PMC10071242 | ||
Availability of data and materials | Not applicable. | PMC10071242 | ||
Declarations | PMC10071242 | |||
Ethics approval and consent to participate | The Research and Medical Ethics Committee of the Integrated Area of Talavera de la Reina approved this study (protocol code: 12/2018). All participants received verbal and written information about the study and gave their written informed consent. | PMC10071242 | ||
Consent for publication | Not applicable. | PMC10071242 | ||
Competing interests | Meditouch | The authors declare no potential conflicts of interest with respect to the research, authorship, or publication of this article. The Meditouch | PMC10071242 | |
References | PMC10071242 | |||
Background | Studies have shown that supplementation with recombinant human GH (rh-GH) during ovarian stimulation (OS) may improve the ovarian response and clinical outcomes of IVF. However, it remains unclear whether GH is associated with the ploidy status of embryos, and therefore, is unable to explain the underlying reason for the effect of GH on IVF outcomes. This study aimed to investigate whether GH supplementation in women with advanced maternal age (AMA) during OS is related to an increased probability of obtaining euploid blastocysts. | PMC10585718 | ||
Methods | ANEUPLOIDY | This was a single center retrospective cohort study. The data of all women aged 38–46 years who underwent their first preimplantation genetic testing for aneuploidy (PGT-A) cycle between January 2021 and June 2022 were reviewed. Patients in the GH group received 4 IU/day subcutaneous GH supplementation from the beginning of OS to the trigger day, and patients in the control group did not. A total of 140 patients in the GH group and 272 patients in the control group were included after 1:2 propensity score matching. | PMC10585718 | |
Results | The baseline and cycle characteristics between the two groups were similar. The proportion of cycles which obtained euploid blastocysts was significantly higher in the GH group than that in the control group (41.43% vs. 27.21%, P = 0.00). The GH group had a significantly higher euploid blastocyst rate per cohort (32.47% vs. 21.34%, P = 0.00) and mean euploid blastocyst rate per cycle (per biopsy cycle 0.35 ± 0.40 vs. 0.21 ± 0.33, P = 0.00; per OS cycle 0.27 ± 0.38 vs. 0.16 ± 0.30, P = 0.02). However, the benefit of GH was more significant in patients aged 38–40 years, but not significant in patients aged 41–46 years. Pregnancy outcomes were similar between the two groups after embryo transfer. | PMC10585718 | ||
Conclusions | GH supplementation during OS is associated with a significantly increased probability of obtaining euploid blastocysts in women aged 38–40 years, but this benefit is not significant in women aged 41–46 years. Our results explained the underlying reason for the effect of GH on IVF outcomes in existing studies, and might be helpful for AMA patients undergoing PGT-A cycles to obtain a better outcome meanwhile to avoid over-treatment. | PMC10585718 | ||
Trial registration | NCT05574894, | PMC10585718 | ||
Keywords | PMC10585718 | |||
Background | congenital disabilities | PREGNANCY LOSS | With the postponement of women’s marriage and childbearing in recent decades, the number of women with advanced maternal age (AMA) seeking in vitro fertilization (IVF) has increased significantly. However, owing to the reduction of euploid embryos in women with AMA, they experience a higher prevalence of IVF failure, pregnancy loss, and congenital disabilities in offspring compared to younger women [The growth hormone (GH) is a polypeptide hormone secreted by the anterior pituitary gland, which plays a role in promoting cell division and growth by directly binding to receptors on target cells or stimulating the liver to secrete insulin-like growth factor (IGF) [In recent years, studies have shown that supplementation with recombinant human GH (rh-GH) during OS may improve the ovarian response and clinical outcomes of IVF. A study of preovulatory ovarian follicles and follicular fluid showed that GH could upregulate the expression of follicular-stimulating hormone (FSH) and luteinizing hormone (LH) receptors in granulosa cells in women aged 39–45 years, thereby improving ovarian response and pregnancy outcomes in this population [Obtaining euploid embryos is a prerequisite for healthy live births and is considered the primary goal for OS in women with AMA. It is important to evaluate the effect of GH supplementation on the ploidy status of blastocysts in this population and therefore explain the underlying reason for the effect of GH on IVF outcomes. Thus, the present study aimed to compare the euploidy status of blastocysts obtained from patients with AMA with or without GH supplementation during OS. | PMC10585718 |
Methods | PMC10585718 | |||
Study design and population | This cohort study retrospectively collected the data of all women aged 38–46 years who underwent their first OS cycle scheduled for PGT-A in Shanghai JiAi Genetics and IVF Institute from January 2021 to June 2022 in the institutional electronic database. Each participant was required to have a body mass index (BMI) in the normal range (18.50–24.0 kg/mThe women included were offered GH or not during OS at the discretion of the attending physicians or subject to the wishes of the couple after extensive counseling. Patients in the GH group received 4 IU/day subcutaneous rh-GH (Saizen, Changchun GeneScience, Changchun, China) from the beginning of OS to the trigger day, which was a routine dosage of GH supplementation in our IVF center and was also suggested by other studies [The study protocol was approved by the Research Ethics Committee of the Shanghai JiAi Genetics and IVF Institute (Approval Number: JIAI E2022-14, Study ID: JIAI E2022-022, NCT05574894, | PMC10585718 | ||
IVF-ET procedures and PGT-A | ovarian hyperstimulation | OVARIAN HYPERSTIMULATION | OS, oocyte retrieval, fertilization, blastocyst culture, endometrial preparation, embryo transfer, and luteal phase support were performed according to standard protocols in our IVF center, as previously described in detail [Briefly, a flexible antagonist protocol for controlled ovarian hyperstimulation was used for each participant, with recombinant human FSH (Gonal-f; Merck Serono, Geneva, Switzerland) or human menopausal gonadotropin (HMG, Livzon, Zhuhai, China) initiated on the 2nd or 3rd day of the menstrual cycle at a starting dose of 150–300 IU/day, adjusted for age, BMI, antral follicle count (AFC), FSH, and anti-Mullerian hormone (AMH) levels. Gonadotropin-releasing hormone antagonist (Cetrotide; Merck Serono) was administered at a dose of 0.25 mg/day when the dominant follicle reached 14 mm in size or the serum E2 level reached 350 pg/ml. This treatment continued until the leading follicle reached 18 mm or two follicles reached 16 mm in size. Subsequently, a dose of 5,000–10,000 IU of human chorionic gonadotropin (Livzon, Zhuhai, China) was administered as a trigger, and oocytes were retrieved 36 h later.Intracytoplasmic sperm injection and blastocyst culture were performed for all participants following IVF laboratory guidelines, and next-generation sequencing-based PGT-A was administered to all blastocysts obtained using a NextSeq CN500 sequencer (Illumina, Inc. San Diego, CA, USA) according to the manufacturer’s instructions [ | PMC10585718 |
Study outcomes | heartbeat and breath | The primary goal of a scheduled PGT-A cycle is to obtain euploid blastocysts for transfer. Therefore, the primary outcome was the proportion of cycles which obtained euploid blastocysts, calculated as the number of cycles with ≥ 1 euploid blastocyst divided by the total number of OS cycles in a cohort. Secondary outcomes included euploid blastocyst rate per cohort (total number of euploid blastocysts in a cohort/total number of biopsied embryos in the same cohort) and euploid blastocyst rate per cycle (number of euploid blastocysts obtained in a cycle/number of blastocysts obtained in the same OS cycle). The mean euploid blastocysts per cycle were calculated separately considering the OS cycle and biopsy cycle. A biopsy cycle was defined as the OS cycle with blastocysts for biopsy and genetic testing. If no blastocysts or euploid blastocysts were obtained after OS, the euploidy rate of this cycle was zero. Additional outcomes of interest included embryo implantation, clinical pregnancy, and ongoing pregnancy. Embryo implantation was defined as positive serum β-HCG levels 14 days after embryo transfer. Clinical pregnancy was defined as the visualization of the gestational sac on ultrasonography. Ongoing pregnancy was confirmed if a pulsating fetal pole was present at 12 weeks of gestation. Live birth was deliveries ≥ 22 weeks gestation with heartbeat and breath. All transfer outcomes were followed up until June 2023. | PMC10585718 | |
Statistical analysis | ANEUPLOIDY | PSM was used to identify the patients with or without GH supplement who were most similar in baseline and stimulation characteristics and to adjust for confounders related to aneuploidy. The variables in the PSM included indications for PGT-A, age, BMI, number of previous OS cycles, basal estradiol (E2), FSH, AMH, and AFC levels, duration of stimulation, and total dosage of gonadotropins. The PSM was carried out using a caliper width of 0.2 of the standard deviation (SD) of the logit of the propensity score and 1:2 ratio by nearest neighbor matching. Women who were not matched were excluded from further analyses.According to the data from our IVF center, approximately 25% of patients with AMA can obtain ≥ 1 euploid blastocyst in a PGT-A cycle (unpublished data). As this proportion is supposed to be 40% in patients with AMA after GH supplement according to a previous study [Values are presented as average ± SD for continuous data and compared using Student’s t-test or Mann–Whitney U test. Categorical variables were expressed as frequency and percentage, and between-group differences were assessed using Pearson’s chi-square test or Fisher’s exact test as appropriate. Subgroup analyses were performed stratified by age groups [ | PMC10585718 | |
Results | PMC10585718 | |||
Baseline and cycle characteristics of patients in the GH and control groups before and after PSM | RPL | RECURRENT PREGNANCY LOSS, PREGNANCY LOSS | A total of 692 women with AMA undergoing PGT-A were included in this study, including 143 in the GH group and 549 in the control group (Fig.
Flowchart detailing the distribution of the two study groups. GH = growth hormone; OS = ovarian stimulation; PGT-A = preimplantation genetic screening; PS = propensity score; SET = single embryo transfer
Baseline and cycle characteristics of the GH and control groups before/after propensity score matchingGH = growth hormone; PSM = propensity score matching; BMI = body mass index; OS = ovarian stimulation; PGT-A = preimplantation genetic screening; AMA = advanced maternal age; PL = pregnancy loss; RIF = repeated implantation failure; RPL = recurrent pregnancy loss; FSH = follicle stimulating hormone; LH = luteinizing hormone; E2 = estradiol; AMH = anti-Mullerian hormone; AFC = antral follicle count; PN = pronuclei. | PMC10585718 |
PGT-A results between the GH and control groups | REGRESSION | There was no significant difference in the biopsy cycle rates between the two groups (Table
PGT-A cycle outcome of women in the GH and control groups after PSMNo. of OS cycles obtaining no blastocysts,n (%)32(22.86)68(25.00)a. Pearson’s chi-square test was used to compare the between group difference of the number of the denoted row and the sum of the other two rows. The results were presented as p-value, odds ratio (95% confidence intervals). GH = growth hormone; OS = ovarian stimulation; PGT-A = preimplantation genetic screening; PSM = propensity score matchingSubgroup analyses indicated that for patients aged 38–40 years, the proportion of cycles with euploid blastocysts (66.67% vs. 43.59%, P = 0.00), the euploid rate of blastocysts per embryo biopsied (50.58.47% vs. 29.01%, P = 0.02), the mean blastocyst euploid rate calculated per OS cycle (0.40 ± 0.37 vs. 0.24 ± 0.33, P = 0.01) and per biopsy cycle (0.46 ± 0.37 vs. 0.31 ± 0.35, P = 0.01) were significantly higher in the GH group than those in the control group. However, the benefit of GH on these outcome parameters was not significant in patients aged 41–43 years and 44–46 years (Table
Subgroup analyses of PGT-A outcomes between the GH and control groups after PSMAge 44–46 years(n = 71)* Data are presented as number of cycles with obtained euploid blastocysts/number of OS cycles, (%)GH = growth hormone; OR = odds ratio; CI = confidence intervalMultivariate logistic regression analyses showed that GH supplementation was an independent factor in improving the acquisition of euploid embryos in patients with AMA aged 38–46 years (adjusted risk ratio [aRR] = 2.273, P = 0.001). Stratified analyses indicated the significant benefit ofGH supplementation was more pronounced in women aged 38–40 years (aRR = 2.653, P = 0.006). However, there was no association between GH supplementation and the acquisition of euploid embryos in patients aged41–43 years and 44–46 years (Table
Logistic regression analyses of variables associated with the acquisition of euploid embryos**Confounders including GH supplement, age, AMH, AFC, BMI, number of previous OS cycles, duration of stimulation, total dosage of gonadotropins, and estradiol on trigger day, were evaluated using multivariate logistic regression models (backward LR). Covariates were retained in the final adjusted model if they were significantly associated with the outcome parameters (P < 0.05). For the subgroup of women aged 44–46 years, none of the aforementioned variables were significantly associated with the acquisition of euploid embryos; therefore, they are not presented in the table. GH = growth hormone; OR = odds ratio; CI = Confidence interval; AFC = antral follicle count; BMI = body mass index; AMH = anti-Mullerian hormone; OS = ovarian stimulation | PMC10585718 | |
Clinical outcomes after embryo transfer | By the end of the study, 47 patients in the GH group and 67 patients in the control group had undergone embryo transfer cycles, all of which were single euploid blastocyst transfers. Implantation, clinical pregnancy, ongoing pregnancy and live birth outcomes were similar between the GH and control groups (Table
Clinical outcomes of embryo transferGH = growth hormone; NS = not significant | PMC10585718 | ||
Discussion | ANEUPLOIDY | In this retrospective cohort study with PSM, GH supplementation was associated with higher proportion of cycles with euploid blastocysts, euploidy blastocyst rate per cohort, and mean euploid blastocyst rate per cycle in women with AMA. Moreover, GH supplementation was an independent factor in improving the acquisition of euploid blastocysts in this population, and the effect was age-dependent, with greater benefits in patients aged 38–40 years. However, for patients aged ≥ 41 years, GH supplementation had no significant effect on increasing the acquisition of euploid embryos during OS. Euploid blastocysts obtained with or without GH supplementation did not differ significantly in clinical outcomes after embryo transfer.To the best of our knowledge, this is the first study to investigate the effect of GH in IVF from the perspective of the ploidy status of embryos in patients with AMA. Currently, only one study has evaluated the effect of GH supplementation during PGT-A cycles in 41 patients without a priori suspicion of poor outcomes based on their clinical parameters [As the aneuploidy rate of oocytes increases with age, we stratified the patients by age to investigate whether the effect of GH treatment was age dependent. We found that GH supplementation benefitted the acquisition of euploid embryos in women aged 38–40 years, but the effect was not significant in patients aged ≥ 41 years. These results are consistent with those of a previous study by Keane et al. [We compared the implantation, clinical pregnancy, ongoing pregnancy and live birth rates of euploid embryos obtained with or without GH supplementation, and the results showed no differences. Meanwhile, the gestational age at delivery and birth weight of newborns were similar between the two groups (Table There were no significant differences between the two groups in the proportion of patients with mosaic embryos (9/140, 6.43% vs.18/272, 6.62%) and the rate of mosaic embryos per biopsy (9/231, 3.89% vs. 30/492, 6.10%, Table Our study has some limitations. First, this study was observational and retrospective in nature, which can only provide correlation instead of causation of the benefit of GH on embryo euploidy status. Second, there was a potential selection bias as patients in the two groups were not randomized. Although all the first PGT-A cycles during the study period were reviewed and were 1-to-2 matched using propensity scoring, some potential unknown or unmeasured covariates may have led to incomplete matching. For example, affordability may also have been a confounder since patients were required to pay for GH, and it was not possible to be evaluated in our study. Third, this was a single center study which limited the sample size. Although the dataset was relatively large and sufficient patients were included in the two groups, caution need to be made to interpret the age group analyses due to the reduced case number per subgroup, especially for patients with ultra-advanced ages (≥ 44 years). Patients in this age group seeking IVF do not account for a high proportion of patients in IVF centers but were clinically challenging, with an extremely low chance of live birth [ | PMC10585718 | |
Conclusions | In conclusion, GH supplementation during OS is associated with a significantly increased probability of obtaining euploid blastocysts in women aged 38–40 years, but this benefit is not significant in patients aged 41–46 years. Our results might be helpful for AMA patients undergoing PGT-A cycles to obtain a better outcome and meanwhile to avoid over-treatment. Future RCTs are needed to confirm our results and the effect of GH in women aged ≥ 41 years requires further investigation. | PMC10585718 | ||
Acknowledgements | The authors thank Professor Jiangfeng Ye Ph.D. for her help with the statistical analysis of the data. | PMC10585718 | ||
Authors’ contributions | XS and LL contributed to the conception and design of the study. YS, MX, YX, and CL acquired and analyzed the data. JF, MX, and CL completed the PGT. YS and MX drafted the article. All authors contributed to manuscript revision, read, and approved the submitted version. | PMC10585718 | ||
Funding | This study is supported by the Special Project for Clinical Research in the Health Industry of the Shanghai Municipal Health Commission (20224Y0218, 20204Y0071). The funding source had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. | PMC10585718 | ||
Data Availability | The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Upon publication, we will share the individual participant data and study protocols that support the findings of this article, provided that they have been deidentified, with no specific end date for availability. These materials will be made available to researchers who submit a sound proposal. Proposals should be directed to xiaoxi_sun@aliyun.com. | PMC10585718 | ||
Declarations | PMC10585718 | |||
Competing interests | The authors declare no competing interests. | PMC10585718 | ||
Ethics approval and consent to participate | The study protocol was approved by the Research Ethics Committee of the Shanghai JiAi Genetics and IVF Institute (Approval Number: JIAI E2022-14, Study ID: JIAI E2022-022, NCT05574894, | PMC10585718 | ||
Consent for publication | Not applicable. | PMC10585718 | ||
References | PMC10585718 | |||
Background: | Parkinson’s disease, PD | Coinvestigators listed in the Supplementary Material.Apomorphine sublingual film (SL-APO) and subcutaneous apomorphine (SC-APO) have been used for the treatment of OFF episodes in Parkinson’s disease (PD). No study has prospectively compared efficacy and safety of these formulations. | PMC10741320 | |
Objective: | PD | To compare SL-APO with SC-APO for treatment of OFF episodes in PD. | PMC10741320 | |
Methods: | PD | An open-label, randomized, crossover study assessed SL-APO versus SC-APO in patients with PD and OFF episodes ( | PMC10741320 | |
Results: | Propensity score matching applied on 159 patients (STN-DBS | PMC10741320 | ||
Conclusions: | depression | We report Class IIb evidence of beneficial effects of STN-DBS on quality of sleep at 36-month follow-up, which were associated with QoL improvement independent of depression and dopaminergic medication. Our study highlights the importance of sleep for assessments of DBS outcomes. | PMC10741320 | |
Results: | MOVEMENT DISORDER | No difference was observed between SL-APO and SC-APO for change from predose to 90 minutes postdose in Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part III score at week 4 (primary endpoint), assessed by a blinded rater (–13.6 vs. –13.8, respectively; | PMC10741320 | |
Conclusions: | Patients reported overall preference for and greater satisfaction with SL-APO over SC-APO. | PMC10741320 | ||
INTRODUCTION | Parkinson’s disease, PD | Oral carbidopa/levodopa (CD/LD) is the cornerstone of Parkinson’s disease (PD) treatment [Apomorphine, a D1-family and D2-family agonist with an affinity similar to dopamine, is used for the treatment of OFF episodes in patients with PD [SC-APO is a reliable, effective treatment option for managing OFF episodes; however, its utilization has been limited. SC-APO is administered by subcutaneous injection and involves a multistep product assembly for administration, which may be challenging for patients experiencing decreased motor function [ | PMC10741320 | |
METHODS | PMC10741320 | |||
Study design and participants | PD, ; mouth, idiopathic PD | DISORDER, SECONDARY PARKINSONISM | This multicenter, open-label, randomized, crossover study assessed SL-APO compared with SC-APO in patients with PD and OFF episodes and was conducted in Europe (EudraCT: 2016-003456-7). Herein we provide a brief review of methods, with full methodology available in the Supplementary Methods. Eligible patients were ≥18 years of age with idiopathic PD responsive to and being treated with stable doses of CD/LD and any additional PD medications for ≥4 weeks (>8 weeks for monoamine oxidase-B inhibitors), were stage 1–3 by modified Hoehn and Yahr scale when ON, had ≥1 OFF episode/day and ≥2 h of total daily OFF time, and had a Mini-Mental State Examination score >25. Key exclusion criteria included atypical or secondary parkinsonism; major psychiatric disorder; mouth cankers/sores; prior device-aided treatments; permanent discontinuation of prior SC-APO administration or prior exposure to SL-APO; currently taking selective 5-HTThe study was designed, conducted, and monitored in accordance with the World Medical Association Declaration of Helsinki (1989) and International Council for Harmonisation guidelines. The study protocol and study procedures were approved by institutional review boards and independent ethics committees at each study site (Supplementary Methods). | PMC10741320 |
Procedures | PD | The study consisted of open-label dose-optimization and open-label treatment phases (Study design. SL-APO (Dose optimization of SC-APO (Initially, use of the antiemetic domperidone was optional if clinically warranted and was not to be used prophylactically. After a protocol amendment, domperidone use remained optional but could also be used prophylactically or if clinically warranted at the discretion of the investigator. If initiated, antiemetic therapy was discontinued when judged clinically appropriate.After a 3- to 7-day washout, patients entered the treatment phase and were randomized in a 1 : 1 ratio to 4 weeks of treatment with the optimized dose of SL-APO or SC-APO, followed by a washout and 4 weeks of crossover treatment. Patients continued their regular PD medication regimen and could self-administer study treatment for ≤5 OFF episodes per day when needed. Clinic visits occurred every 2 weeks, with the patient presenting in a practically defined OFF episode. | PMC10741320 | |
Evaluations | BLIND | The primary efficacy endpoint was change from predose to 90 min postdose in MDS-UPDRS Part III score after 4 weeks of dosing in each crossover period, assessed in clinic by a rater blinded to treatment assignment. The blind was maintained by ensuring that the rater did not witness in-clinic dosing, that visible injection sites were covered, and that source data and electronic clinical report forms were protected. Because SL-APO can leave a blue residue on the tongue, a sublingual placebo was administered upon SC-APO in-clinic dosing. Secondary endpoints were evaluated in a hierarchical order and included the following: investigator-rated durability of response (defined as investigator-confirmed achievement of a FULL ON within 30 min postdose and maintenance of that response at 90 min postdose); treatment preference for SL-APO, measured with a 9-item patient self-reported Treatment Preference Questionnaire (TPQ [Consort flow diagram. Pharmacokinetic (PK) concentration-time data for apomorphine and metabolites (apomorphine sulfate, norapomorphine) were evaluated and PK parameters, including maximum observed plasma concentration (CUnblinded safety evaluations conducted during both study phases included assessments of AEs, physical examinations, 12-lead electrocardiograms, and vital signs. | PMC10741320 | |
Statistical analysis | SECONDARY | The primary objective of the study was to demonstrate superiority of SL-APO over SC-APO in improving motor function assessed as change from predose to 90 min postdose in MDS-UPDRS Part III score for SL-APO compared with SC-APO after 4 weeks of dosing in each crossover period (primary endpoint). The sample size calculation was based on randomization of 106 patients in the dose-optimization phase and ≥80 patients in the treatment phase, with ≥55 patients expected to complete treatment; this would provide 90% power to detect a mean treatment difference between SL-APO and SC-APO of 5.5 points for the change in MDS-UPDRS Part III score, assuming a standard deviation (SD) of 12 points for the period differences in treatment. The primary endpoint was analyzed in the treatment phase modified intention-to-treat (mITT) population (all patients who were randomized and received ≥1 dose of either study drug in the treatment phase) and was compared between treatment groups using a linear mixed model, with treatment group, visit week (0, 2, 4), treatment by visit week interaction, treatment phase sequence, and period as fixed factors and the week 0 visit predose MDS-UPDRS Part III score as a covariate. The primary and secondary endpoints were tested in a hierarchical order to maintain an overall type I error rate of 0.05. AEs were summarized descriptively for both the dose-optimization and treatment phase safety populations (all patients who received ≥1 dose of either study drug for each phase). | PMC10741320 | |
RESULTS | PMC10741320 | |||
Efficacy | Movement Disorder, Parkinson’s Disease Rating Scale, SE | MOVEMENT DISORDER, SECONDARY | The primary endpoint of change from predose to 90 min postdose in MDS-UPDRS Part III score at week 4 was comparable for SL-APO and SC-APO (least squares [LS] mean [standard error], –13.6 [1.5] vs. –13.8 [1.5]; Change from predose in MDS-UPDRS Part III score at week 4 over time (treatment phase mITT population). Data represent MDS-UPDRS Part III scores achieved with the optimized dose of each apomorphine formulation at week 4 of the treatment phase. LS, least squares; MDS-UPDRS, Movement Disorder Society Unified Parkinson’s Disease Rating Scale; mITT, modified intention-to-treat; SC-APO, subcutaneous apomorphine; SE, standard error; SL-APO, apomorphine sublingual film.The secondary endpoints of investigator- and patient-rated durability of response were comparable between SL-APO and SC-APO at week 4 (investigator-rated predicted response rate, 11.8% vs. 10.6% [Investigator- and patient-rated durability of responseThe secondary endpoint of patient preference for SL-APO over SC-APO was evaluated using the TPQ at study end, after patients completed both treatment periods. When patients were presented with the following statement: “Overall, the treatment I prefer for my OFF episodes is,” 72.2% preferred SL-APO compared with SC-APO/no preference (95% CI, 61.9–82.6; | PMC10741320 |
PK | The t | PMC10741320 | ||
DISCUSSION | nausea, lip swelling, stomatitis, nausea and vomiting, vomiting, PD | MOUTH ULCERATION, STOMATITIS, INJECTION SITE HEMATOMA, SECONDARY, INJECTION SITE REACTION, BLIND, EVENTS, INJECTION SITE ERYTHEMA | This open-label, randomized, crossover study was designed to meet regulatory requirements as a registrational study in the European Union. The purpose was to compare efficacy, safety, tolerability, and patient preference for SL-APO and SC-APO, with the 90-min primary endpoint chosen based on prior PK studies [Prior studies have demonstrated a rapid onset of effect of SL-APO as early as 15 min postdose, which was chosen as the earliest time point against which differences between SL-APO and SC-APO were measured in this study [The 90-min time point chosen for the primary endpoint was based on differences in PK observed between SL-APO and SC-APO and previous findings from SC-APO studies. In a randomized, open-label, 3-way crossover study, CClinical guidance extrapolated from the results of this study suggest that while dose optimization is highly individualized, generally a factor of 5 to 10 can be used to determine a comparable dose when converting a patient from SC-APO to SL-APO. Based on prior PK studies [An overall preference for SL-APO was observed based on the TPQ. These results are particularly robust considering the crossover design of the study, in which patients were treated with both formulations and provided their response regarding preference for treatment at study end. This finding was supported by a numerically higher level of satisfaction with SL-APO compared with SC-APO on the TSQM for convenience and global satisfaction. Although the TPQ was developed for this study and has not been formally validated, alignment between the TPQ and TSQM findings supports the content validity of the TPQ. These results align with a previous finding that, for OFF treatment modes associated with AEs, patients with PD reported a preference for a hypothetical sublingual film associated with mouth/lip sores versus a hypothetical injectable medication associated with injection site reactions [The safety profiles of SL-APO and SC-APO were generally comparable and well tolerated. During dose optimization, rates of overall AEs, serious AEs, and AEs leading to discontinuation were comparable between SL-APO and SC-APO. The most common AEs were also generally similar. However, higher rates of nausea were observed during dose optimization with SL-APO (31.4%) compared with SC-APO (22.7%). Despite higher rates of nausea for patients treated with SL-APO, the majority of events were mild or moderate in severity and did not lead to discontinuation of treatment, and none were considered serious. Rates of vomiting during dose optimization were relatively low. Daily solicitation of tolerability during SL-APO dose optimization may have contributed to a bias towards higher rates of nausea in patients receiving SL-APO during that study phase, as rates of nausea were comparable during the treatment phase (SL-APO, 14.1%; SC-APO, 15.7%). Although domperidone use could have mitigated nausea and vomiting, its use was not standardized across the study; however, the proportions of patients who did not utilize antiemetics were similar during treatment with SC-APO and SL-APO in both phases of the study. Further, it is not possible to draw conclusions about prophylactic versus reactive antiemetic use as the database did not capture the time or reason an antiemetic was taken. A previously published study demonstrated that among 43.7% of patients who did not use an antiemetic during SL-APO dose optimization, 86.2% achieved an effective and tolerable dose [Expected differences in route of administration AEs were also noted. Among patients treated with SC-APO, 6.2% of patients reported injection site erythema and 2.1% reported injection site hematoma during dose optimization, and 7.1% and 27.1%, respectively, reported these events during the treatment phase. In patients treated with SL-APO, no individual events in the category of oral application-related AEs occurred at a rate >3% during either study phase; the most frequent oral application-related AEs were lip swelling, mouth ulceration, and stomatitis. The combined incidence of all oral AE terms was 1.0% during dose optimization and 9.9% during the treatment phase. The shorter, 4-week duration of exposure in this study may have influenced the occurrence of oral AEs as compared with a previously published SL-APO study that involved an open-label titration phase followed by a 12-week double-blind maintenance phase [There are several limitations to consider. The primary and secondary endpoints were assessed using a statistical hierarchy. As the primary endpoint was not statistically significant, all subsequent endpoints were evaluated descriptively. Efficacy endpoints were assessed by a rater blinded to treatment assignment, and every effort was made to maintain that blind by preventing the rater from witnessing dosing, covering visible evidence of route of administration, and protecting source data and electronic clinical report forms. However, the open-label administration of SL-APO and SC-APO may have introduced bias. As a direct head-to-head study, there was no placebo group and all patients were on active treatment. As previously discussed, there was no specific data collection method for the use of antiemetics; therefore, the impact of antiemetic use on nausea and vomiting rates is confounded. As SL-APO dose optimization was performed at home by patients, investigators may have been more inclined to increase the dose, whereas this bias may not have been evident for SC-APO dosing performed in clinic under supervision. For a dose to be considered optimal, FULL ON had to occur within 30 min, which may have impacted the optimal dose. Furthermore, doses to which patients were optimized may reflect the investigator and patient’s levels of experience with the treatments, as some patients had experience with SC-APO before study enrollment. Similar to previous studies, patients in the current study administered apomorphine approximately 1.6 times per day, despite reporting four OFF episodes per day, demonstrating that patients do not administer treatments at the same frequency at which they experience OFF episodes [In conclusion, SL-APO demonstrated comparable efficacy for the treatment of OFF episodes associated with PD and a similar safety profile to SC-APO, with patients reporting an overall preference for and greater satisfaction with SL-APO. | PMC10741320 |
Supplementary Material | PMC10741320 | |||
Supplementary Material | Click here for additional data file. | PMC10741320 | ||
ACKNOWLEDGMENTS | The study was supported by funding from Sumitomo Pharma America, Inc. (Marlborough, MA, USA). The authors would like to thank all coinvestigators, including Dr. Valentina Leta, for their contributions to the study. Medical writing and editorial assistance were provided by Maureen Wallace-Nadolski, PhD, and Jessica Deckman, PhD, CMPP, of The Lockwood Group (Stamford, CT, USA) and were supported by funding from Sumitomo Pharma America, Inc. (Marlborough, MA, USA). | PMC10741320 | ||
SUPPLEMENTARY MATERIAL | The supplementary material is available in the electronic version of this article: | PMC10741320 | ||
FUNDING | The study was supported by funding from Sumitomo Pharma America, Inc. (Marlborough, MA). | PMC10741320 | ||
CONFLICTS OF INTEREST | Parkinson’s, Zambon | FOX | FS is an Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer review and has received grants and/or research support from Zambon and honoraria or consultation fees from Bial, Biogen, Britania Pharmaceuticals, Chiesi, Cynapsus Therapeutics, Kyowa Kirin, Lundbeck, NeuroDerm, Sunovion Pharmaceuticals Inc., and Zambon.OR has received grants and/or research support from Agence Nationale de la Recherche (ANR), CHU de Toulouse, France-Parkinson, INSERM-DHOS Recherche Clinique Translationnelle, Michael J. Fox Foundation, and Programme Hospitalier de Recherche Clinique, European Commission (FP7, H2020) and honoraria or consultation fees from AbbVie, Adamas, Acorda, Aguettant, Alkahest, AlzProtect, ApoPharma, AstraZeneca, Bial, Biogen, Britannia Pharmaceuticals, Bukwang, Cerevel, Clevexel, Irlab, Eli-Lilly, Lundbeck, NeuroDerm, ONO Pharma, Orion Pharma, Osmotica, Oxford Biomedica, Pfizer, Prexton Therapeutics, Sanofi, Servier, Sunovion Pharmaceuticals Inc., Theranexus, Takeda, Teva Pharmaceuticals, UCB, Watermark Research, XenoPort, XO, and Zambon.WP has received grants and/or research support from Michael J. Fox Foundation, EU FP7 & Horizon 2020; personal fees from AC Immune, Alterity, AbbVie, Affiris, Bial, Biogen, Britannia Pharmaceuticals, Eli Lilly, Lundbeck, NeuroDerm, Neurocrine, Roche, Sunovion Pharmaceuticals Inc., Stada, Takeda, UCB, and Zambon; and royalties from Cambridge University Press, Oxford University Press, Thieme, and Wiley Blackwell.KRC is an Editorial Board member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer review and has received grants and/or research support from BIAL, EU Horizon 2020, Parkinson’s UK, NIHR, Parkinson’s Foundation, and Wellcome Trust and honoraria or consulting fees from 4D Pharma, AbbVie, Acadia, Bial, Boehringer Ingelheim, Britannia Pharmaceuticals, Cynapsus Therapeutics, GKC, Kyowa Kirin, Lobsor Pharmaceuticals, Novartis, Profile Pharma, Roche, Scion, SK Pharma, Stada, Sunovion Pharmaceuticals Inc., Theravance Biopharma, UCB Pharma, and Zambon.JK has received honoraria or consultation fees from AbbVie, Bial, Biogen, Desitin, Esteve, Licher MT, Medtronic, NeuroDerm, Novartis, STADA, UCB Pharma, and Zambon; in addition, he is Specialty Chief Editor in LLM has received compensated advisory services, consulting, research grant support, or speaker honoraria from AbbVie, Bial, Italfarmaco, NeuroDerm, Roche, Stada, Sunovion Pharmaceuticals Inc., UCB Pharma, and Zambon.YZ, AB, and EP were employees of Sunovion Pharmaceuticals Inc. at the time the analyses were conducted.SW is an employee of Sumitomo Pharma America, Inc. | PMC10741320 |
DATA AVAILABILITY | Access to de-identified participant data will be provided after a research proposal is submitted online ( | PMC10741320 | ||
REFERENCES | PMC10741320 | |||
Background | toxicity | DRUG INTERACTIONS | Combinations of drugs are becoming increasingly common in oncology treatment. In some cases, patients can benefit from the interaction between two drugs, although there is usually a higher risk of developing toxicity. Due to drug–drug interactions, multidrug combinations often exhibit different toxicity profiles than those of single drugs, leading to a complex trial scenario. Numerous methods have been proposed for the design of phase I drug combination trials. For example, the two-dimensional Bayesian optimal interval design for combination drug (BOINcomb) is simple to implement and has desirable performance. However, in scenarios where the lowest and starting dose is close to being toxic, the BOINcomb design may tend to allocate more patients to overly toxic doses, and select an overly toxic dose combination as the maximum tolerated dose combination. | PMC9979534 |
Method | To improve the performance of BOINcomb in the above extreme scenarios, we widen the range of variation of the boundaries by setting the self-shrinking dose escalation and de-escalation boundaries. We refer to the new design as adaptive shrinking Bayesian optimal interval design for combination drug (asBOINcomb). We conduct a simulation study to evaluate the performance of the proposed design using a real clinical trial example. | PMC9979534 | ||
Results | Our simulation results show that asBOINcomb is more accurate and stable than BOINcomb, especially in some extreme scenarios. Specifically, in all ten scenarios, the percentage of correct selection is higher than the BOINcomb design within 30 to 60 patients. | PMC9979534 | ||
Conclusion | The proposed asBOINcomb design is transparent and simple to implement and can reduce the trial sample size while maintaining accuracy compared with the BOINcomb design. | PMC9979534 | ||
Keywords | PMC9979534 | |||
Introduction | toxicity, cancer | CANCER, DISEASES | Drug combination therapy provides an important method for the treatment of difficult diseases such as cancer. The purpose of drug combination therapy is to induce synergistic therapeutic effects, increase the combined dose intensity, and achieve better therapeutic effects without cross-toxicity. The purpose of a drug combination dose escalation trial is to identify the maximum tolerated dose combination (MTDC) based on a prespecified target toxicity rate. In a single-drug dose escalation trial, toxicity is typically assumed to increase with an increasing dose. However, the order of toxicity between dose combinations in two-drug combination trials is only partially known. If the dose of one drug in the combination increases while that of the other drug decreases, it is unknown whether the toxicity increases or decreases (Fig. Partial toxicity order as shown. The probability of toxicity is greater for the A1B2 combination than for A1B1. In drug combination trials, the order of toxicity for all dose combinations is not entirely clear (e.g., between A2B1 and A1B2)Example of equivalent contour lines based on DLT probability for multiple dose combinationsThe rest of this paper is organized as follows. In Section 2, the BOIN design, the BOINcomb design, and the improved BOINcomb design, denoted as asBOINcomb design, are presented. In Section 3, a simulation study is used to evaluate our proposed design. The results of the simulation study are also analyzed. Section 4 uses a trial example to illustrate our proposed design. Section 5 provides some brief discussions. Finally, a summary is presented in Section 6. | PMC9979534 |
Methods | PMC9979534 | |||
BOIN design | toxicity | The BOIN (Bayesian optimal interval) design is a Bayesian model-assisted phase I dose-finding design proposed by Liu and Yuan Y (2015). The design is simple and flexible and performs comparably to model-based designs [if if otherwise, i.e., The trial continues until the prespecified sample size is exhausted or the trial is stopped due to excessive toxicity.The boundary designation algorithm for the BOIN design aims to minimize incorrect decisions on dose assignment. It makes three assumptions:where Under the Bayesian model, the three hypotheses are given equal prior probabilities, denoted as The BOIN design is easy to implement and has comparable performance to that of existing one-dimensional phase I dose-finding design [ | PMC9979534 | |
BOINcomb design | The two-dimensional BOIN design for drug combination trials is based on an extension of the one-dimensional design. The details are as follows. Assume that The rules of BOINcomb are as follows:Treat the first cohort of subjects with the lowest dose combination (1, 1).Assuming that the current cohort is treated with dose combination (If If Otherwise, if This process continues until the total sample size is exhausted.During dose escalation and de-escalation, if there are multiple optimal dose combinations in sets | PMC9979534 | ||
Simulation studies | PMC9979534 | |||
Simulation studies | DLTs | After determining the optimal bounding range (∆According to Fig. PCS comparison of BOINcomb and asBOINcomb designs for simulation studies with multiple sample sizesAccording to Fig. Comparison of PNMTDC of BOINcomb and asBOINcomb designs for simulation studies with multiple sample sizesAccording to Fig. Comparison of DLTs for simulation studies with BOINcomb and asBOINcomb designs at multiple sample sizesCombining the three metrics of PCS, PNMTDC, and DLTs, asBOINcomb has better accuracy than BOINcomb, especially in some extreme scenarios, or equivalently, asBOINcomb can achieve performance comparable to BOINcomb with a smaller sample size. | PMC9979534 | |
Trial example | toxicity, TNBC, Toxicity, thyroid cancer | TRIPLE-NEGATIVE BREAST CANCER, SOLID TUMOR, T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA, REGRESSION, TUMOR GROWTH, THYROID CANCER | To further evaluate the proposed strategy, we applied the proposed design to a clinical trial of PF03084014 combined with doxorubicin for the treatment of advanced triple-negative breast cancer (TNBC). PF-03084014 is a reversible, noncompetitive, and selective secretase inhibitor that blocks the NOTCH signaling pathway. In preclinical studies, this combination has demonstrated anticancer efficacy in solid tumor models, such as advanced thyroid cancer and sclerofibrosarcoma, and in T-cell acute lymphoblastic leukemia. In TNBC patient-derived and cell lineage xenograft models, the combination of PF-03084014 with doxorubicin greatly improved the inhibition of tumor growth [In this phase I study (A8641016), patients with advanced TNBC were evaluated for safety, tolerability, pharmacokinetics, and antitumor efficacy. The goal of the study was to determine the MTDC of the drug PF03084014 when combined with the chemotherapy drug doxorubicin. The dose exploration component used a modified probability interval technique based on a 2 × 3 matrix design to evaluate toxicity. On day 1 of each 21-day cycle, oral PF-03084014 was coadministered with intravenous doxorubicin twice a day.To redesign the trial, we fitted logistic regression models to the data observed in this PF03084014 with doxorubicin combination trial. Table Toxicity scenarios for PF03084014 in combination with doxorubicinThe target toxicity probability was set to 0.33, the maximum sample size was 30 patients, the cohort size was 3, and the first group of patients was treated with the lowest dose combination (1, 1). After the parameter set simulation, the optimal parameters Example of PF03084014 in combination with doxorubicinAs shown in Fig. Example results of the PF03084014 and doxorubicin combination trial“-” represents a dose combination that was not administered in the trial. The dose combination (2, 2) is selected as the MTDC. As shown in Figs. | PMC9979534 |
Discussion | From statistical and clinical viewpoints, the proposed combination designs are simple and easy to understand. But there are some practical or ethical issues that have not been considered in actual trials. The above design aims to find individual MTDC in the drug combination trial and is not suitable for finding MTDC profiles. This is a topic of our future research. | PMC9979534 | ||
Conclusion | We improve the two-dimensional Bayesian optimal interval design by proposing adaptively-shrinking dose escalation/de-escalation boundaries, which converge with increasing sample size. In addition, we introduce the parameter | PMC9979534 |
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