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2.1. Patient Characteristics | kidney stones, kidney abnormalities | KIDNEY STONE | This RCT was approved by the Institutional Review Board of Applied Science Private University (ASU) (protocol number 2020-PHA-16) and undertaken between October 2020 and December 2020. The clinical trial was conducted following the Helsinki Declaration. Each individual who was enrolled provided informed consent for this clinical trial. With an average baseline age of 38.37 ± 9.77 years, volunteers included were Jordanian and from ASU staff and their families (ranging from 30 to 66). Eligible participants were included in the trial depending on a diagnosis of VDD confirmed by medical consultants at Ibn Al-Haytham clinical laboratories. Because prolonged VD3 administration is related to the formation of kidney stones, patients with kidney abnormalities were excluded from the study [ | PMC10005440 |
2.2. Intervention | Before and after the VD3 supplement, baseline and follow-up values of anthropometric and clinical parameters were collected. At the conclusion of the 8-week interventional phase, the subjects underwent a 2-week washout phase before and following VD3 administration. VD3 is a fat-soluble vitamin with a long half-life; a washout period was achieved to avoid the potential effect of its cumulative dose. Then, all participants’ follow-up measurements were obtained. An independent statistician developed a computer-generated randomization process. According to the consortium chart ( | PMC10005440 | ||
2.3. Anthropometric Measurement | This RCT was conducted throughout the winter of 2020 at the ASU Pharmacy school laboratories to minimize seasonal fluctuations in vitamin D assays in the blood [ | PMC10005440 | ||
2.4. Clinical Parameter Assays | ab181421, TNF-α, ab178013 | Serum assay of clinical parameters was collected into labeled Eppendorf tubes at Ibn Al-Haytham Hospital, Clinical Laboratories Department, Jordan.The chemiluminescence immunoassay LIAISON 25OHD assay (DiaSorin, Saluggia, Italy) measured total serum 25OHD. The assay quantifies serum 25OHD and is cross-reactive with 25OHD2 and 25OHD3. Its lower limit was 4 ng/mL. An enzyme immunoassay kit measured serum leptin levels (leptin EIA-5302, DRG Diagnostics, Marburg, Germany). Test sensitivity was 0.1 ng/mL. An enzyme immunoassay kit tested serum PTH levels (PTH Intact EIA-3645, DRG Diagnostics, Marburg, Germany). The sensitivity was 1.57 pg/mL. The calcium-ARSENAZO kit (M11570i-15) and the phosphorus phosphomolybdate/Uv kit (M11508i-18, BioSystems, Barcelona, Spain) were used to measure the levels of calcium and phosphorus (PO4) in serum. Serum IL-6 concentration was measured using the Human ELISA KIT (ab178013, Abcam, Newark, NJ, USA). Using a Human ELISA Kit, serum IL-10 was measured (ab185986, Abcam). Human ELISA KIT assessed serum IL-1β (ab214025, Abcam). The Human ELISA KIT assay measured serum TNF-α (ab181421, Abcam). | PMC10005440 | |
2.5. Statistical Analysis | SPSS version 27 for Windows was used to execute the statistical analysis. A paired | PMC10005440 | ||
3. Results | PMC10005440 | |||
3.1. Baseline Values of the Participants | A total of 75 out of 127 (59.1%) participants in the trial adhered to the protocol and finished the intervention period that lasted for 8 weeks. As indicated in Participants’ average age was (38.37 9.77). When measured at baseline, all other serum markers had mean values that were within normal limits. Descriptive analysis for anthropometric parameters, including BMI (27.90 ± 4.76), waist and hip circumferences, and WHR, are shown in | PMC10005440 | ||
3.2. Baseline Clinical Characteristics | The baseline mean value for serum 25OHD was (17.29 ± 6.18) ng/mL (all participants were VD deficient). None of the participants presented in this trial with a baseline serum 25OHD level equal to or greater than 30 ng/mL. All participants’ baseline values of all serum parameters, including PTH, Ca, and PO | PMC10005440 | ||
3.3. Connection between Selected Cytokine Variables and 25OHD Concentrations | In this trial, selected proinflammatory cytokines (IL-1β, TNF-α, and IL-6) and anti-inflammatory cytokine (IL-10) showed statistically significant intercorrelations (The Pearson correlation analysis showed no intercorrelation between serum cytokine levels in the VD3 group, as shown in | PMC10005440 | ||
3.4. Changes in the Serum Levels of 25OHD and PTH | Paired sample | PMC10005440 | ||
3.5. Changes in the Serum Levels of Selected Cytokines Associated with Cytokine Storm at Baseline and 10-Week Follow-Up | At the end of this study, a paired | PMC10005440 | ||
3.6. Stepwise Regression Analysis | REGRESSION | The multivariate stepwise regression analysis revealed significant mediating factors (IDVs) on the circulatory levels of selected cytokines associated with CS at the 10-week follow-up supplementation of VDRegarding the TNF/IL-10 ratio, WHR only was selected by the stepwise regression model among all IVDs to be involved in the positive relationship between elevated 25OHD levels and the TNF/IL-10 ratio (R = 0.348, R | PMC10005440 | |
4. Discussion | chronic kidney disease, IBS, HD, chronic renal impairment, diabetic | CHRONIC RENAL IMPAIRMENT, FLUID OVERLOAD, INFLAMMATORY RESPONSES, CHRONIC DISEASES, INFLUENZA A, CHRONIC INFLAMMATION | At the end of the trial, high doses of VDResults of the current trial were consistent with a prior RCT [Previous clinical trials have typically been conducted under a treatment protocol close to or similar to our protocol, but they have been scarce. After extensive review, some clinical research studies were conducted under a protocol similar to this trial: four trials. In a trial conducted for 12 weeks on early chronic kidney disease [Patients with chronic renal impairment, such as hemodialysis patients, have elevated plasma IL-6 levels due to chronic inflammation and fluid overload. Reduced IL-6 clearance is noted with compromised kidney function, contributing to its retention. Therapeutic hemodialysis triggers inflammatory responses and increases IL-6 production [The same dose of VD3 (50,000 IU per week) for 12 weeks lowered IL-6 levels in another RCT that aimed to examine the effect of VD3 and omega-3 fatty acid cosupplementation as an adjuvant chemotherapy [It is important to note here that the observations of Al-Haidari and Khalighi were from trials conducted on patients under the influence of the treatment protocol for chronic diseases. In the Khalighi trial, all IBS patients received antispasmodic medication (Mebeverine, 135 mg twice daily) besides VDSome studies have linked changes in the serum levels of IFN-γ and IL-10 observed after VDRCTs conducted on diabetic hemodialysis (HD) patients [Considering the impact of a given dose in the different protocols, past clinical trials utilized different doses and durations of VDOn the other hand, age and body weight factors are separately involved in the association between 25OHD and other proinflammatory cytokines (IL-1β and TNF). Elevated IL-6 and other cytokines observed in this trial contradict our previous hypothesis and are challenging to explain biologically. Considering whether the study sample is healthy people or patients, the effect of VDFurther, the presence or absence of typical risk factors did not obscure the U-shape association [Although it has been established that VD3 supplementation reduces the incidence of influenza A [Another piece of evidence that came from a recent study showed that VDNevertheless, IL-6 decreases DC maturation and chemokine-receptor 7 expressions and may sometimes operate as an anti-inflammatory modulator [Contraindicating results might contribute to the varying doses and durations of VD | PMC10005440 |
5. Conclusions | High doses of VD | PMC10005440 | ||
Author Contributions | D.A.B.: Conceptualization, methodology, writing original article, data curation, investigation and review/editing the article. A.A. (Anas Abed): investigation, and review/editing. B.A.M.: methodology, writing and review/editing the article. A.A. (Ahmad Aljaberi): formal analysis and review/editing the article. A.S.: formal analysis and review/editing the article. M.H.: validation and review/editing the article. A.R.A.: resources, validation, and review/editing the article. M.A.: resources and writing and review/editing the article. S.A.-S.: resources and writing and review/editing the article. M.A.-S.: Conceptualization, methodology, supervision, writing original article, project administration, data curation, investigation and review/editing the article. All authors have read and agreed to the published version of the manuscript. | PMC10005440 | ||
Institutional Review Board Statement | Not applicable. | PMC10005440 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10005440 | ||
Data Availability Statement | Not applicable. | PMC10005440 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC10005440 | ||
References | tumor | TUMOR, VITAMIN D DEFICIENCY | Consort flow diagram for the study.Frequencies and percentages of anthropometric and lifestyle variables at baseline (Abbreviations: VDStatistical description of anthropometric parameters at baseline level (n = 75).Abbreviations: SD, standard deviation; BMI, body mass index; WHR, waist/hip ratio.Descriptive summary of clinical variables at baseline (n = 75).Abbreviations: 25OHD, 25 hydroxy vitamin D; POLevels of selected cytokines involved in the cytokine storm of COVID-19 at baseline in the entire study population with vitamin D deficiency (n = 75).Abbreviations: IL-1β, interleukin-1 beta; IL-6, interleukin 6; IL-10, interleukin 10; TNF-α, tumor necrosis-alpha; SD, standard deviation. Note: Correlation of selected cytokine with baseline and follow-up 25OHD levels.Note: R, correlation coefficient.Changes in the serum levels of 25OHD and PTH.Abbreviations: PChanges in the serum levels of selected cytokines associated with cytokine storm at baseline and 10-week follow-up.Abbreviations: PSignificant correlations of cytokine and ratio levels with trial variables at follow-up.Abbreviations: WHR, waist/hip ratio. | PMC10005440 |
Background | depression, PTSD, anxiety | ADVERSE EFFECTS | Educating dentists in treatment methods for dental anxiety would increase the patients’ access to treatments that are important to their oral health. However, to avoid adverse effects on comorbid symptoms, involvement by a psychologist has been considered necessary. The objective of the present paper was to evaluate whether a dentist could implement systematized treatments for dental anxiety without an increase in comorbid symptoms of anxiety, depression or PTSD. | PMC10288821 |
Methods | anxiety | A two-arm parallel randomised controlled trial was set in a general dental practice. Eighty-two patients with self-reported dental anxiety either completed treatment with dentist-administered cognitive behavioural therapy (D-CBT, | PMC10288821 | |
Results | PTSD, Depression, Anxiety, anxiety | -11 | An Intention-To-Treat analysis indicated reduced dental anxiety scores by the Modified Dental Anxiety Scale (median MDAS: 5.0 (-1,16)). The median scores on the Hospital Index of Anxiety and Depression (HADS-A/D) and the PTSD checklist for DSM-IV (PCL) were reduced as follows: HADS-A: 1 (-11, 11)/HADS-D: 0 (-7, 10)/PCL: 1 (-17,37). No between-group differences were found. | PMC10288821 |
Conclusions | depression, PTSD, anxiety | ADVERSE EFFECTS | The study findings support that a general dental practitioner may treat dental anxiety with Four Habits/Midazolam or D-CBT without causing adverse effects on symptoms of anxiety, depression or PTSD. Establishing a best practice for treatment of patients with dental anxiety in general dental practice should be a shared ambition for clinicians, researchers, and educators. | PMC10288821 |
Trial registration | The trial was approved by REC (Norwegian regional committee for medical and health research ethics) with ID number 2017/97 in March 2017, and it is registered in clinicaltrials.gov 26/09/2017 with identifier: NCT03293342. | PMC10288821 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12903-023-03061-4. | PMC10288821 | ||
Keywords | Open access funding provided by University of Oslo (incl Oslo University Hospital) | PMC10288821 | ||
Background | phobias, phobia, anxiety, PTSD, depression | Dental anxiety has a high prevalence, and this combined with a high impact on oral health, constitutes a serious public health challenge [Cognitive behavioural therapy (CBT) is recognized as the treatment of choice for specific phobias, including the most severe form of dental anxiety, dental phobia [The daily management of patients with dental anxiety in general dental practices often includes the use of sedatives [Awareness of the importance of adequate communication and functional dentist-patient relationships for treatment outcome in dentistry is growing [Although studies on dentist-administered dental anxiety treatments are promising, little is known about how the presence of comorbid psychological symptoms may influence treatment effect, or how dental anxiety treatment may influence pre-existing problems. Knowledge on how these symptom levels fluctuate during and after dental anxiety treatment by a dentist in general dental practice is also lacking. In addition, we know very little about how the dentist-patient relationship influence outcome of dental anxiety treatments. Accordingly, the present study tested the following hypothesis: 1. High score on comorbid symptoms (anxiety, depression, and PTSD) will not negatively affect the dental anxiety treatment effect measured by the reduction in dental anxiety. 2. No increase in symptoms of general anxiety, depression, or PTSD will be observed following systematic dental anxiety treatment administered by a dentist in a general dental practice. 3. The patient rated dentist-patient relationship will be of importance to the outcome of treatment by D-CBT and Four Habits/midazolam. | PMC10288821 | |
Methods | The trial was approved by REC (Norwegian regional committee for medical and health research ethics) with ID number 2017/97 and it is registered in clinicaltrials.gov with identifier: NCT03293342. | PMC10288821 | ||
Data | psychiatric, anxiety | ADVERSE REACTIONS, RECRUITMENT, TSD | The data presented in this article was collected in a general dental practice in a rural Norwegian town. A total of 96 patients were admitted to the study between September 2017 and March 2020. Recruitment was conducted by a research assistant. In a baseline session the research assistant provided more detailed information about the trial and also about the public treatment alternative in interdisciplinary teams. Thereafter, the participants signed an informed consent form, completed the questionnaires, and were randomly allocated by the assistant to either the D-CBT (The four habits modelThe table describes the main aspects of the Four Habits Model and the skills required for proper useThe treatment conditions were completed in four (Four Habits/Midazolam treatment condition) or five (D-CBT treatment condition) visits, with a total duration of 300 min in both methods. The methods were detailly described in manuals. An English version of the D-CBT manual along with an e-learning programme in Norwegian is freely available at the Faculty of Dentistry, University of Oslo [The participating patients were offered two alternatives following the interventions: 1) A referral for dental treatment with a general dental practitioner of their choice at full payment, or 2) A referral for further dental anxiety treatment and free dental treatment at a specialised dental anxiety clinic.Prior to the study, an emergency plan was made that included access to a local psychiatric centre. This was a precautionary measure in the case that strong and acute psychological adverse reactions would arise in response to the treatment. Data collection and storage was on the TSD (Tjeneste for Sensitive Data) facilities, owned by the University of Oslo, operated, and developed by the TSD service group at the University of Oslo, IT-Department. | PMC10288821 |
Sample of patients | anxiety | The inclusion criteria for the RCT study were as follows: (i) self-reported dental anxiety at a level of severity that affected the participant’s ability to receive dental treatment, and (ii) the ability to communicate fluently in Norwegian. The patients were mainly self-referred (In the present study, sample size calculations were done with a significance level of 0.05 (α = 0.05) and a power set to 0.8 (β = 0.20). Sample size was estimated from the DAS values among patients with dental anxiety but without diagnosed odontophobia reported in a Norwegian study conducted by Kvale and colleagues [ | PMC10288821 | |
One dentist treated all the patients | anxiety | Patients in both treatment conditions were treated by the same dentist, a 40-year-old Norwegian woman, who had completed her dental studies in Oslo 12 years prior to the study. Although she had no relevant specialisation, she had completed a theoretical exam on CBT treatment for dental anxiety (equivalent to a 40-h course) and participated in additional video-assisted training in the practical use of CBT, provided by the co-authors. The RCT study was conducted in a dental practice setting that included two other general dental practitioners, two specialists (surgery and endodontics), and one dental hygienist. The clinic had a shared waiting room. | PMC10288821 | |
Video-evaluation | All sessions were videotaped. A random selection of tapes was evaluated by the co-authors (TW and BT) to assess adherence to manuals in both treatment conditions. | PMC10288821 | ||
Background measures | Anxiety, anxiety, traumatic, PTSD, depression, Depression, Post-Traumatic Stress Disorder | Age, sex, and years since last completed dental treatment were registered at enrolment along with symptoms of anxiety, depression and Post-Traumatic Stress Disorder (PTSD). Self-report scales were employed. All the scales are extensively used worldwide and have been shown to be valid and reliable (see details in the description of each scale).Participants that reported a traumatic incidence were asked to complete the PTSD checklist for DSM-IV (PCL), version PCL-S. The scale assesses PTSD-symptoms through 17 questions with five possible answers, resulting in a sum score of 17 to 85. Cut-off in a non-clinical population is proposed to be 35 [Symptoms of anxiety and depression were assessed with the Hospital Anxiety and Depression Scale (HADS) developed by Zigmond et al. in 1983 [ | PMC10288821 | |
Outcome measures | Anxiety, anxiety | The change in dental anxiety from pre- to one-year after-treatment was used as a measure of treatment efficiency. Dental anxiety was measured before, after and one year after treatment with the Modified Dental Anxiety Scale (MDAS) and the Index of Dental Anxiety and Fear (IDAF-4C). MDAS mentions 5 potentially frightening stimuli which are scored on a five-point-scale. A sum score (range 5–25) of 15 plus/19 plus indicate high/extremely high dental anxiety [To measure possible negative psychological effects of treatment, the changes in psychometric measures (HADS described above) from pre- to one-year after-treatment were calculated. PTSD-symptoms were compared between start and end of intervention.The patient-dentist relationship was mapped with the Working Alliance Inventory for clients (WAI) which consists of 12 statements to be evaluated on a 7-item scale. It measures the following dimensions: 1. The relationship 2. The agreement on goals and 3. The agreement on tasks between the therapist and the patient [Ten aspects believed to be of importance to treatment success were defined by the authors in collaboration with 2 professors of psychology (Table Aspects of treatment considered to be of importance to treatment effectThe table describes the aspects of treatment included in the questionnaire “The Patient Evaluation” | PMC10288821 | |
Missing data | Fourteen patients did not complete the treatment. In addition, 5 patient records were lost at the storage facility (see details in Additional file [Additional file | PMC10288821 | ||
Statistical analysis | The data was not normally distributed (see additional file for normality tests [Additional file All analyses were done using the Stata/SE 16.0 statistical software. | PMC10288821 | ||
Discussion | phobia, anxiety, traumatic, PTSD, depression | EVENT, DISORDERS | In the present study comorbid symptoms of anxiety, depression or PTSD did not inhibit the treatment efficiency of two dentist-administered dental anxiety treatment methods. Nor did the treatment delivered coincide with an increase in symptoms of anxiety, depression, or PTSD in neither method. On the contrary, comorbid symptoms decreased during the dental anxiety treatment. Both dentist-administered CBT-treatment and Four Habits Model/midazolam-treatment proved to reduce dental anxiety effectively. The patients evaluated aspects relevant to the dentist-patient relationship to be the most important factors for treatment effect. The available emergency plan in case of acute psychological distress never had to be put into action.The use of validated instruments renders it possible to compare the present findings with findings in other relevant studies, while the standardized treatment protocols enhance reproducibility. Self-report measures are used in this study as well as in many comparable studies [Only one dentist treated all the patients. With this study design dentist variability could not influence the findings, which strengthens the inferences that can be drawn from the study. However, at the same time the study design limits the generalizability of the findings to other dentists. Yet, as both treatment methods were delivered with strict adherence to detailed treatment manuals, replication of treatments by other dentists is facilitated.The presence of drop-out and lost records could bias all repeated scores. The LOCF-design used to replace missing data is conservative and might underestimate study findings. It is a strength to the study that variability of the treatment effects over time was assessed.The symptoms of PTSD were measured only among patients that reported to have experienced a traumatic event and were removed from the questionnaire one year after treatment. This weakened the findings based on this variable.The present study confirms the presence of high comorbid symptomatology in patients with strong dental anxiety reported by Halonen et al. [The hypothesis “High score on comorbid symptoms (anxiety, depression, or PTSD) will not negatively affect the dental anxiety treatment effect measured by reduction in MDAS-score” was supported. No association was found between psychological symptoms and the effect of the dental anxiety treatment. This is in line with earlier studies on psychologist-administered or -assisted dental anxiety treatments [The hypothesis “No increase in symptoms of general anxiety, depression, or PTSD will be observed following systematic dental anxiety treatment administered by a dentist in a general dental practice” was supported. This finding contrasts with a recent systematic review in which Bürklein et al. In this paper it is recommended that when high levels of dental anxiety are associated with a long avoidance (> 2 years) a psychologist or psychiatrist should be consulted. This is justified by the authors due to the high frequency of other psychological disorders seen in patients with elevated dental anxiety. However, Bürklein et al. had no findings themselves, or reference to findings by other researchers, that support this recommendation [In the present study the dental anxiety treatment was followed by a decrease in the psychological symptom load. This leans support to previous findings on the effect of dental anxiety treatment on comorbid psychological symptoms. In a Swedish study comparing systematic desensitization by psychologist with sedation treatment in patients with severe dental anxiety (mean avoidance six years), positive generalization effects were reported [These findings support that dentist-administered treatments could safely serve as a cost-effective first line treatment of dental anxiety of differing severity. This could greatly increase access to treatment for patients in need. In the present study a second line treatment option involving a psychologist was available and referrals were made for about one third of the patients. Educating dentists to do first line treatments for dental anxiety should not be expected to eradicate the need for dental anxiety/dental phobia treatments by psychologist/psychiatrist. It may however relieve the pressure on such specialised services since a lower level of care appears to be satisfactory for the majority of the patients.The hypothesis “The patient-rated dentist-patient relationship will be of importance to the outcome of treatment by D-CBT and Four Habits/midazolam” was partially supported. Ceiling effects have been reported in relation to the Working Alliance Inventory as well as in other tools for measuring relationship/alliance [ | PMC10288821 |
Conclusions | depression, anxiety | ADVERSE EFFECTS | In conclusion, efficient dental anxiety treatment could be administered by a trained dentist by at least two methods available in a general dental practice. The treatments investigated were not associated with adverse effects and were adequate for patients with severe dental anxiety and for patients with elevated symptoms of anxiety, depression or PTSD.More detailed research on relations between changes would be interesting, with larger groups of patients with different severities of initial conditions.Dentists that deliver such treatments need training, including guidance in relational skills. Systematic dental anxiety treatment by a dentist can be effective and important for good oral health in a lifetime perspective. Hence, establishing a best practice for treatment of patients with dental anxiety in general dental practice should be a shared ambition for clinicians, researchers, and educators. | PMC10288821 |
Acknowledgements | We would like to thank professor Asle Hoffart and professor Olav Vassend for important contributions to study design, as well as Kari Laudal for her invaluable assistance throughout the course of the study and Anne Birgit Vintermyr for her important influence in ensuring that the study continued undisturbed through administrative challenges. | PMC10288821 | ||
Authors’ contributions | MSH contributed to conception, design, data acquisition and interpretation, statistical analysis, drafted and critically revised the manuscript. TW contributed to conception, design, data interpretation, drafted and critically revised the manuscript. BS contributed to conception, design, data interpretation, drafted and critically revised the manuscript. All authors read and approved the final manuscript. | PMC10288821 | ||
Funding | Open access funding provided by University of Oslo (incl Oslo University Hospital). The study was funded by the Norwegian Directorate of Health. | PMC10288821 | ||
Availability of data and materials | The data that support the findings of this study are available from the Dental Faculty at the University of Oslo, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from Mariann Saanum Hauge or prof. Tiril Willumsen upon reasonable request and with permission of the Dental Faculty at the University of Oslo. | PMC10288821 | ||
Declarations | PMC10288821 | |||
Ethics approval and consent to participate | The trial was approved by REC (Norwegian regional committee for medical and health research ethics) with ID number 2017/97. A written informed consent was obtained from all participants. All methods were carried out in accordance with relevant guidelines and regulations in the Declaration of Helsinki. | PMC10288821 | ||
Consent for publication | Not applicable. | PMC10288821 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10288821 | ||
References | PMC10288821 | |||
Background | SRS | BRAIN METASTASES, SOLID TUMORS | Comparative prospective data regarding different radiosurgery (SRS) modalities for treating brain metastases (BMs) from solid tumors are not available. To investigate with a single institute phase III randomized trial whether SRS executed with linac (Arm-B) is superior to a dedicated multi-source gamma-ray stereotactic platform (Arm-A). | PMC9906937 |
Methods | brain failure, radionecrosis | SOLID TUMORS | Adults patients with 1–4 BMs from solid tumors up to 30 mm in maximum diameter were randomly assigned to arms A and B. The primary endpoint was cumulative incidence of symptomatic (grade 2–3) radionecrosis (CIRN). Secondary endpoints were local progression cumulative incidence (CILP), distant brain failure, disease-free survival (DFS), and overall survival (OS). | PMC9906937 |
Results | A total of 251 patients were randomly assigned to Arm-A (121) or Arm-B (130). The 1-year RN cumulative incidence was 6.7% in whole cohort, 3.8% (95% CI 1.9–7.4%) in Arm-B, and 9.3% (95% CI 6.2–13.8%) in the Arm-A ( | PMC9906937 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s13014-023-02216-5. | PMC9906937 | ||
Keywords | PMC9906937 | |||
Introduction | cancer | BRAIN METASTASES, CANCER | The occurrence of brain metastases (BMs) is a challenging issue affecting about 20–40% of cancer patients [ | PMC9906937 |
Methods and materials | PMC9906937 | |||
Study design and patients | SCLC, active extra-cranial disease, brain failure, SRS | ADVERSE EVENT, SCLC, DISEASE, HEMATOLOGIC MALIGNANCY, SOLID TUMORS, SMALL CELL LUNG CANCER | The present is a single institute prospective randomized, double-arms phase 3 trial approved by our institutional review board, registered at the ClinicalTrials.gov site with the number NCT02355613. The trial was approved by the Institutional Review Board, and it was monitored by the institutional Data and Safety Monitoring Board. The study aimed to compare SRS treatments executed on a Gamma-Knife Perfexion unit (Elekta AB, Stockholm, Sweden), Arm-A, or an Edge treatment system (Varian Medical Systems, Palo Alto, USA), Arm-B. All patients provided written informed consent to the treatment and the use of their data for scientific purposes. Eligible patients were aged 18–85 years, Karnofsky performance status (KPS) ≥ 70, histo-pathologically confirmed primary solid tumors, 1–4 BMs up to 30 mm in maximum diameter, recursive partitioning analysis (RPA) class 1–2, estimated survival ≥ 3 months as from disease specific-grade prognostic assessment (DS-GPA) score. Patients with a primary diagnosis of small cell lung cancer (SCLC), hematologic malignancy, pregnancy or prior whole brain radiotherapy were excluded from the enrolment. The administration of bevacizumab (possibly included in some chemotherapy schemes) for at least two months after radiosurgery was another exclusion criterion since potentially altering the RN patterns. Patients could have an active extra-cranial disease, and a systemic agents treatment has been permitted while in the study. The primary endpoint was the occurrence of symptomatic RN in our patients expressed as cumulative incidence (CIRN). Symptomatic RN was defined as grade 2 (moderate symptoms; corticosteroids indicated), grade 3 (severe symptoms; intervention indicated), and grade 4 (severe symptoms; immediate intervention indicated) as for Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Radiologically, RN was defined as the radiographic evidence of lesion on postcontrast T1MRI not visible on T2MRI sequences (T1/T2 mismatch), absence of perfusion on perfusion MRI, and/or absence of uptake on 11CMETPET. Secondary endpoints were cumulative incidence of local progression (CILP), distant brain failure (DBF), disease-free survival (DFS), and overall survival (OS). CILP was evaluated (per-lesion) measuring lesion volume variation according to the Response Assessment in Neuro-Oncology (RANO) Working Group [The total beam-on time was recorded as complementary endpoints as efficiency indicators. The total treatment time was not effectively recorded for all patients and will not be reported. | PMC9906937 |
Study design and randomization | The primary endpoint was the cumulative incidence of patients experiencing symptomatic RN (grade 2–4). A superiority design was assumed. Symptomatic RN was expected at around 10% at one year for Arm-A. Considering a rate of ~ 1% for Arm-B, 250 patients were required for the study to have a power of 80% to demonstrate this difference with a two-sided | PMC9906937 | ||
Treatment regimens | tumor, isodose, T1MRI, OSMS, SRS | SEPARATION, TUMOR, METASTASES | Concerning patient immobilization and treatment planning imaging, in Arm-A, a Leksell frame system was applied, and a volumetric MRI was performed. The target volume was defined as the contrast-enhancing tumor on the volumetric T1MRI. Prescription doses were 24 Gy for BMs ≤ 20 mm, and 20 Gy for lesions 21–30 mm, delivered at the 50% isodose line. No margins from target volume have been applied, and no image-guided performed before SRS treatment. The radiation dose was delivered with multi-isocenter plans so that the 50% isodose line conformed to 100% of the target volume. A basal CT scan without contrast and a post-contrast volumetric T1MRI were acquired for treatment planning in Arm-B. All the patients were immobilized with an open-face thermoplastic mask. The gross tumor volume (GTV) was defined as the contrast-enhancing tumor on the volumetric T1MRI. The planning target volumes (PTV) were generated by adding an isotropic margin of 2 mm from GTV. All plans were optimized with multiple isocentres (one per lesion) except for the cases where the separation between different metastases was inferior to 3 mm. In these cases, a shared isocentre was used. A single dose of 24 Gy was prescribed at the mean dose to PTV for metastases with a diameter ≤ 20 mm, while a dose of 20 Gy would have been prescribed for BMs with a diameter of 21–30 mm. The planning objective was that > 95% of PTV received 95% of the prescribed dose (PTV V95% > 95%) and that > 98% of GTV covered by 98% of the prescribed dose. SRS was delivered on an unit equipped with the high definition multileaf collimator with a leaf thickness at the isocentre in the target region of 2.5 mm. The Volumetric Modulated Arc Therapy technique was used, and flattening filter-free beams of 6 or 10 MV were selected for all patients. Image-Guided RT (IGRT) was performed with kV-CBCT, and patient repositioning was provided in six dimensions using an integrated six degrees of freedom treatment couch. The Optical Surface Monitoring Solution (OSMS, Varian Medical Systems, Palo Alto, US) performed real-time patient tracking during the delivery. For both arms, dose constraints to the organs at risk were the following: brain stem: V | PMC9906937 |
Follow-up and outcomes | toxicities, SRS | RECURRENCES, DISEASE PROGRESSION, ADVERSE EVENT, BRAIN | Clinical and radiological evaluations have been performed at baseline, one month after treatment, and every 3 months after that, or until disease progression; they included history and physical examination, blood tests, and KPS. Hematologic and non-hematologic toxicities were graded according to Common Terminology Criteria for Adverse Events version 3.0. Brain MRI was performed aiming to differentiate post-treatment RN or disease progression. Methionine-CT/PET was performed in those cases with doubt images. An expert neuro-radiologist blindly assessed the response. Local recurrences were treated, and treatments could include surgery, SRS, or systemic agents if feasible. New distant BMs distinct from the treated sites were treated with SRS or WBRT in cases of leptomeningeal diffusion. | PMC9906937 |
Statistical analysis | primary tumor, death, SRS | EVENT, DISEASE, LUNG METASTASES, PRIMARY TUMOR, METASTASES | Time to RN was defined as starting from the day of SRS up to the date of the MRI evaluation. Time to progression was defined as the interval from the date of SRS to the documentation of progression and evaluated for CNS progression (DBF), local progression and DFS, according to the different kinds of failures. Local progression and RN were computed on a per-lesion basis, whereas all other analyses were on a per-patient basis. OS was defined as the interval from SRS to death of any cause. The impact of RN and local progression was estimated by competing risk analysis and cumulative incidence approach considering death as the competing event [The difference in time to RN and local progression was compared between treatment arms using the method developed by Gray [Variables considered were prescribed dose, number, and the dimension of CNS lesions. As further clinical predictors, gender, KPS score (1 for 70, 2 for 80, and 3 for 90–100), histology of primary tumor (non-lung vs lung metastases), stage of disease (1 for stages I and II, and 2 for stages III and IV), presence of extra-cranial metastases (yes/no), RPA class (I vs II), presence of systemic therapy (yes/no), number of BMs (1 for single lesions, 2 for more), and dose prescription were considered as categorical variables. Target volume and diameter were treated as continuous variables.For each variable, HR and For all endpoints, All analyses were conducted using the Stata software (StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC). | PMC9906937 |
Results | PMC9906937 | |||
Patients and tumor characteristics | NSCLC, Renal carcinoma cancer, tumor, HCC, Hepatocellular carcinoma, RCC, SRS | TUMOR, BRAIN METASTASES, NON SMALL CELL LUNG CANCER, NSCLC, METASTASES, RCC | Between October 2014 and June 2020, 251 patients for 449 treated BMs were enrolled and randomly assigned to Arm-A (121) or Arm-B (130), as shown in Fig. CONSORT flow diagram of patients enrolled in the randomized trial comparing Arm-A and Arm-BThe total number of eligible patients was 312, and 19.5% were excluded for the reasons outlined in Fig. Baseline patient, and tumor characteristics stratified for radiosurgery (SRS) modalityNo., Number; pts, Patients; SRS, Radiosurgery; KPS, Karnofsky performance scale; NSCLC, Non small cell lung cancer; RCC, Renal carcinoma cancer; GI, Gastrointestinal; HN, Head and neck; HCC, Hepatocellular carcinoma; GU, Genitourinary; EC met, Extracranial metastases; RPA, Recursive partial analysisThe number of BMs treated was 236 (53.6%) in Arm-A and 213 (47.4%) in Arm-B. Baseline BMs characteristics stratified for SRS modality are shown in Table Brain metastases (BMs) characteristics stratified for radiosurgery treatment armBMs, Brain metastases; No., Number; SRS, RadiosurgeryThe median GTV was 0.38 cmThe dose prescription was 20 Gy in 51 (21.6%) and 24 Gy in 185 (78.4%) lesions in Arm-A, while it was 24 Gy for all 213 treated lesions in Arm-B. The summary of the dosimetric parameters is given in Additional file | PMC9906937 |
Discussion | SRS | MINOR, METASTASES | The results of a randomized phase 3 trial comparing two SRS treatment approaches using different platforms, each characterized by specific features, were reported. The main differing characteristics among the two arms are: (i) the use of a rigid frame system in one and a frameless in the other; (ii) the employ of margins from the GTV in one arm only; (iii) the different dose prescriptions. Concerning the use of the frame, although more modern versions of the multi-source gamma rays system allow the frameless treatments, this is not the usual practice applied, while, on the linacs, the use of masks instead of frames is the most employed mode of patient immobilization in clinical practice. The PTV generation, applying margins from GTV, is, once more related to historical procedures, related to the older linacs technologies, in which the mechanical precision was lower than what is currently available. Nevertheless, the study, which started seven years ago, applied the clinical practice at the design time and was not modified. The evolution of the linac-based techniques would allow today the application of smaller or even zero margins. Such practice is ongoing also in our institute for patients treated out of the protocol but was not included for obvious reasons. However, no increasing RN has been observed despite larger volumes being handled in Arm B. Finally, a two-level dose prescription was also foreseen in the linac arm as per the protocol. In practice, the lesion diameter of the larger metastases in the Arm-B was modestly exceeding the threshold except for one lesion in a multiple lesion patient. This was far from any organ at risk. Since in all cases no dose-volume parameters were at risk for those patients if treated at full dose. For this reason, the Arm-B does not include any patient treated with 20 Gy; we acknowledge this as a minor protocol violation. We also acknowledge that most clinical centers exclusively use one device or the other according to availability. Nevertheless, the availability of the two in a single institute allowed this trial although a better data analysis consistency would be in a multi-institutional investigation. About 20% of eligible patients were excluded from the analysis for the patient cohort for various reasons. This strategy is a formal deviation from the trial protocol, which assumed an intention-to-treat analysis. Nevertheless, due to this significant rate and to minimize potential negative biases, we opted for their exclusion, which is also supported by the fact that most patients did not receive any radiosurgery treatment. We acknowledge this as a protocol deviation and a limitation of the study. The study’s primary endpoint was the RN assessment, assuming a superiority of linac-based SRS compared to the gamma-ray platform. Published data, although not randomized but only comparative, showed a comparable local control using the two modalities for SRS, but a higher risk of RN employing gamma-ray platform compared to linac-based SRS, above all when large BMs are treated, has been recorded [ | PMC9906937 |
Conclusion | BRAIN METASTASES | Given the technical differences between the treatment platforms investigated in this single-institution study, linac-based SRS (Arm-B) did not lead to significantly lower rates of grade 2–3 RN versus the multi-source gamma-ray system (Arm-A) in a population of patients with limited brain metastases of limited volume. No significant difference in patients outcome was observed between both arms. Multicentric prospective randomized trials are needed to confirm this data further. | PMC9906937 | |
Author contributions | Study concept and design: MS, ST, PN. Acquisition, analysis, or interpretation of data: EC, LB, AF, FP, ST, LC, PN. Statistical analysis: VT. Administrative, technical, or material support: LA, CF, MM, LR, DF, GR, FL. Drafting of the manuscript: PN, ST. Critical revision of the manuscript for important intellectual content: All authors. Supervision: MS, PN, ST. All authors reviewed and approved the manuscript. | PMC9906937 | ||
Funding | Research reported in this publication was partially supported by Varian Medical Systems, Palo Alto, USA. Role of funder/sponsor: This manuscript’s contents are solely the responsibility of the authors and do not necessarily represent the official views of Varian Medical systems. The funder had no role in the design, conduct of the trial; collection management, analysis, data interpretation; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. | PMC9906937 | ||
Availability of data and materials | Research data are store in an institutional repository and will be shared upon request to the corrisponding author. | PMC9906937 | ||
Declarations | PMC9906937 | |||
Ethics approval and consent to participate | The present is a single institute prospective randomized, double-arms phase 3 trial approved by our institutional review board, registered at the ClinicalTrials.gov site with the number NCT02355613. The trial was approved by the Institutional Review Board, and it was monitored by the institutional Data and Safety Monitoring Board. All patients provided written informed consent to the treatment and the use of their data for scientific purposes. | PMC9906937 | ||
Consent for publication | Post my preprint. | PMC9906937 | ||
Competing interests | Cancer | CANCER | L.C. acts as Scientific Advisor to Varian Medical Systems and is Clinical Research Scientist at Humanitas Cancer Center. The other authors declare no competing interests. | PMC9906937 |
References | PMC9906937 | |||
Background | Sanfilippo type B, neuronopathic | MUCOPOLYSACCHARIDOSIS (MPS) I | Sanfilippo type B is a mucopolysaccharidosis (MPS) with a major neuronopathic component characterized by heparan sulfate (HS) accumulation due to mutations in the | PMC9843052 |
Methods | In this phase I/II open-label study, patients with MPS type IIIB ( | PMC9843052 | ||
Results | hepatomegaly | RESOLUTION | In the Part 1 dose escalation (30, 100, and 300 mg) phase, a 300 mg dose of tralesinidase alfa was necessary to achieve normalization of HS and HS-NRE levels in the CSF and plasma. In Part 2, 300 mg tralesinidase alfa sustained HS and HS-NRE normalization in the CSF and stabilized cortical gray matter volume (CGMV) over 48 weeks of treatment. Resolution of hepatomegaly and a reduction in spleen volume were observed in most patients. Significant correlations were also established between the change in cognitive AEq score and plasma drug exposure, plasma HS-NRE levels, and CGMV. | PMC9843052 |
Conclusion | Administration of tralesinidase alfa i.c.v. effectively normalized HS and HS-NRE levels as a prerequisite for clinical efficacy. Peripheral drug exposure data suggest a role for the glymphatic system in altering tralesinidase alfa efficacy. | PMC9843052 | ||
Trial registration | Clinicaltrials.gov NCT02754076. | PMC9843052 | ||
FUNDING | BioMarin Pharmaceutical Inc. and Allievex Corporation. | PMC9843052 | ||
Introduction | LSDs, PD, MPS IIIB | LYSOSOMAL STORAGE DISEASES, GENETIC DISORDERS, SANFILIPPO SYNDROME, SANFILIPPO SYNDROME TYPE B | Lysosomal storage diseases (LSDs) are a family of genetic disorders affecting the breakdown and recycling of complex molecules within the lysosomes (Sanfilippo syndrome, or MPS type III, is categorized into 4 subtypes, A–D, according to defects in genes coding for 4 different enzymes. Sanfilippo syndrome type B (MPS IIIB; Online Mendelian Inheritance in Man [OMIM] #252920) is specifically due to mutations in a gene coding for alfa-Endogenous NAGLU contains mannose-6-phosphate (M6P) residues, which enable receptor-mediated endocytosis and targeting to the lysosome where HS is degraded (The objectives of this study were to evaluate the safety, tolerability, and efficacy of tralesinidase alfa administered via an implanted i.c.v. device to patients with MPS IIIB. Here, we report the pharmacokinetics (PK) and pharmacodynamics (PD) results of our clinical investigation of tralesinidase alfa in the treatment of children with MPS IIIB over a 48-week period. Overall, the current study highlights the ability of tralesinidase alfa to alter the natural course of MPS IIIB and suggests that this positive effect may lead to meaningful clinical benefits. | PMC9843052 |
Results | PMC9843052 | |||
Patients’ characteristics and adverse events. | anaphylactic reaction, neurodegenerative disease, choking, vomiting, pyrexia, TEAEs, vomiting, rash, SAEs, pyrexia, infection, angioedema, headache, deaths, hypersensitivity, vomiting, listlessness | ANAPHYLACTIC REACTION, NEURODEGENERATIVE DISEASE, ADVERSE EVENTS, CSF PLEOCYTOSIS, EVENT, UPPER RESPIRATORY TRACT INFECTION, WOUND INFECTION, COMPLICATIONS, EVENTS, CHOKING, BLOOD, INFECTION, ADVERSE EVENT, ANGIOEDEMA, CSF LEAKAGE, HYPERSENSITIVITY, SUBDURAL HYGROMA | Interventional Study 250-201 was divided into Part 1 and Part 2 (Patient 9001 in Study 250-201 Part 1 received 28 weekly doses at 30 mg of tralesinidase alfa, followed by 10 doses at 100 mg, and then 11 doses at 300 mg before being recruited to Study 250-201 Part 2. Patient 9002 received 8, 10, and 19 doses of 30, 100, and 300 mg tralesinidase alfa, respectively, before being recruited to Study 250-201 Part 2, whereas patient 9003 received 20, 10, and 9 doses of 30, 100, and a 300 mg dose of tralesinidase alfa in Study 250-201 Part 1.Characteristics of the participants in Study 250-201 Part 2 are summarized in No deaths occurred during the course of the study. One participant discontinued the study following a serious adverse event (SAE) of subdural hygroma associated with increased intracranial pressure occurring after the seventh dose of tralesinidase alfa. This event was considered common terminology criteria for adverse events (CTCAE) grade 3 and was assessed as unrelated to the study drug or the device by the site’s principal investigator. Clinical symptoms (headache, vomiting, listlessness) resolved within 24 hours with medical management. In total, this patient received only 8 doses of tralesinidase alfa. The most common treatment-emergent adverse events (TEAEs) included vomiting, pyrexia, upper respiratory tract infection, headache, and CSF pleocytosis. SAEs assessed by investigators to be related to the study drug were CSF pleocytosis, vomiting, angioedema, fluctuating consciousness, and pyrexia. SAEs assessed by investigators to be related to the i.c.v. device were infection, device malfunction, CSF leakage, and wound infection. Overall, these TEAEs and SAEs were consistent with known complications of enzyme replacement therapy (ERT), i.c.v. devices, and/or neurodegenerative disease in pediatric populations.Eight hypersensitivity events were reported for 5 patients, 5 events of rash, and 1 event each of angioedema, choking, and maculopapular rash. Blood samples for total IgE, C4, serum tryptase, and drug-specific IgE did not show evidence of anaphylactic reaction in any of these 5 patients for any of the hypersensitivity events observed. | PMC9843052 |
Immunogenicity. | The ADA response was monitored in both CSF and serum during the course of Study 250-201 Part 2 (The only 3 patients with ADA in serum at week 1 were those who had already received tralesinidase alfa treatment in Study 250-201 Part 1 (The largest drop in plasma drug exposure occurred between week 1 and week 5 of Study 250-201 Part 2 (h2B), when the median ADA titer in serum was only 1:405 at week 4. In vitro cell-based studies suggested that antibodies detected in ADA-positive CSF samples were not able to neutralize the uptake of tralesinidase alfa (titers of neutralizing antibodies were <1:100 in ADA-positive CSF samples). | PMC9843052 | ||
Tralesinidase alfa 300 mg normalizes HS and HS-NRE. | Total HS and HS-NRE concentrations in CSF were measured weekly over the course of Study 250-201 Part 1 (During the course of Study 250-201 Part 2, HS-NRE levels in the CSF were normalized after the first 4 weeks of treatment to levels below the 10 ng/mL higher-end-of-normal cutoff (We observed significant correlations between total HS and HS-NRE levels in both CSF and plasma at different time points ( | PMC9843052 | ||
Weekly administration of tralesinidase alfa 300 mg resolves organomegaly. | MPS IIIB | Changes in liver and spleen volumes at weeks 1, 24, and 48 of Study 250-201 Part 2 are depicted in At Study 250-201 Part 1 or Part 2 baseline, spleen volumes in children with MPS IIIB ranged from 0.15 to 0.44 L/m | PMC9843052 | |
Tralesinidase alfa stabilizes brain atrophy in patients with MPS IIIB. | atrophy, MPS IIIB | ATROPHY | CGMV is a measure of the region of the brain most affected by atrophy in patients with MPS IIIB within the age range included in Study 250-201 (Participants enrolled in Study 250-201 lost, on average, 58 mL (median 68 mL) of CGMV from baseline to week 24, but lost only 2 mL from week 24 to week 48, for a total loss of 60 mL (median, 63 mL) from week 1 to week 48 (Nineteen of 22 patients treated with tralesinidase alfa had a total cerebellar volume within normal range at baseline ( | PMC9843052 |
Correlations between tralesinidase alfa exposure and cognitive decline trajectory and plasma HS-NRE levels. | MPS IIIB | DISEASE | A treatment duration of longer than 48 weeks will be needed to establish whether there is a clinically meaningful benefit for cognition related to treatment with tralesinidase alfa. However, to elucidate whether there is early evidence of an effect of tralesinidase alfa on disease trajectory in patients with MPS IIIB, we explored correlations between a change in cognitive AEq and plasma drug exposure, defined as AUCA cumulative plasma HS-NRE concentration was calculated for each participant by integrating plasma HS-NRE concentrations measured every 4 weeks between weeks 12 and 36 of Study 250-201 Part 2. The average drug exposure, i.e., AUC | PMC9843052 |
Correlations of cognitive decline trajectory compared with plasma HS-NRE and cortical gray matter volume. | We also observed an inverse correlation between cumulative plasma HS-NRE concentrations and a change in cognitive AEq score from week 1 to week 48 of Study 250-201 Part 2 (We observed a correlation between a change in the cognitive AEq score over the course of Study 250-201 Part 2 and a change in CGMV during the same period ( | PMC9843052 | ||
Discussion | sleep behavior, hepatomegaly, MPS, MPS IIIB, hepatosplenomegaly, PD, cognitive and communication skills, LSDs, cognitive decline | BRAIN ATROPHY, DISEASE | In the present study, we show that, within weeks of weekly i.c.v. administration, 300 mg tralesinidase alfa could effectively compensate for NAGLU enzymatic activity as demonstrated by the normalization of HS and HS-NRE levels in both the CSF and plasma. Consequently, we observed resolution of hepatomegaly in most of the patients with MPS IIIB within 24 weeks of tralesinidase alfa administration. The presence of ADAs had no effect on HS normalization, hepatomegaly resolution, or the rate of cognitive decline. A longer treatment duration will be needed to fully evaluate the capacity of tralesinidase alfa to positively affect the lives of patients with MPS IIIB. The safety data for tralesinidase alfa (300 mg) administered weekly via i.c.v. infusion are in line with those for other ERTs, especially agents such as cerliponase alfa administered via i.c.v. dosing (Our study of 22 patients with MPS IIIB, aged 25–118 months at baseline, established an effective dose of 300 mg tralesinidase alfa administered i.c.v. as necessary to achieve and sustain normalization of both total HS and disease-specific HS-NRE levels. The normalization of total HS and HS-NRE levels in the CSF provides evidence that tralesinidase alfa can be potentially beneficial to patients with MPS IIIB. While HS-NRE normalization in CSF is critical and a prerequisite for potential efficacy, the concentration of both tralesinidase alfa and the greater dynamic range of measurement of HS-NRE levels in plasma might be indicative of the efficacy of tralesinidase alfa in the CNS (It is classically assumed that CSF flow is unidirectional and, therefore, that proteins directly administered in the CSF should be rapidly transported out of the brain and into the periphery (Our data favor an alternate explanation based on a recently identified pathway regarding the exchange of fluids and solutes from the CSF to the brain; the existence of the glymphatic system has now been established in human brain (The use of both a sedative and a flushing solution could facilitate tralesinidase alfa distribution into the brain, possibly through the perivascular Virchow-Robin spaces (Advances in MRI procedures are enabling new and exciting opportunities to understand the exchange of fluids and solutes from the CSF to the periphery in patients (Our data show that ADAs had no impact on the PK and PD of tralesinidase alfa, unlike what has been reported by others (We believe that the initial accelerated loss of CGMV in the first 24 weeks of Study 250-201 Part 2, i.e., 58 mL on average, versus 22 mL for the same patients in natural history Study 250-901 (The data presented here and in our natural history study (The present analysis has focused on the PK of tralesinidase alfa, the normalization of HS in the CSF and plasma following tralesinidase alfa administration, and its impact on hepatosplenomegaly and stabilization of brain atrophy. In addition, our data show a positive effect of tralesinidase alfa on cognitive function in patients with the highest plasma drug exposure and the lowest levels of HS in plasma. Yet, we recognize the limitations of the current study. In particular, the number of enrolled patients was limited because of the ultra-rare nature of the disease. The treatment duration was only 48 weeks for the great majority of the patients; however, our ongoing clinical study seems to confirm a long-term effect of tralesinidase alfa on cognitive and communication skills. Other long-term effects on sleep behavior and hearing and other quality-of-life measures are being monitored and will be reported in a future publication. Nonetheless, the analyses described in the current study can be applied to other forms of MPS and more broadly to other LSDs with neurological manifestations.In conclusion, the present study demonstrates the ability of 300 mg tralesinidase alfa to normalize HS and HS-NRE levels in CSF, resolve hepatomegaly, and stabilize brain atrophy in patients with MPS IIIB. ADAs did not interfere with tralesinidase alfa efficacy. The safety profile of tralesinidase alfa is consistent with what is expected of a drug administered i.c.v. Plasma drug exposure and plasma HS-NRE levels may indirectly indicate glymphatic function, which may play a role in improved efficacy. Considering the severity of MPS IIIB, it would be unexpected for tralesinidase alfa to provide clinical benefits to every patient, at least in terms of cognitive function. However, the early effect observed in a few patients within only 48 weeks of treatment is very encouraging and warrants further evaluation. In light of the poor and eventually fatal prognosis and the absence of disease-modifying therapies, tralesinidase alfa has the potential to change the course of the disease in children with MPS IIIB. | PMC9843052 |
Methods | PMC9843052 | |||
Study designs. | MPS, MPS IIIB | Interventional study NCT02754076, i.e., Study 250-201, was a phase I/II open-label, dose-escalation (Part 1), and stable-dose (Part 2) study involving males and females between 1 and less than 11 years of age (i.e., 12 months and 132 months) with a confirmed diagnosis of MPS IIIB. Three patients, i.e., patients 9001, 9002, and 9003, were enrolled in Study 250-201 Part 1 and received weekly escalating doses, i.e., 30, 100, and 300 mg of tralesinidase alfa via an i.c.v. device such as the Ommaya reservoir and a catheter implanted into the lateral ventricle. Twenty-three patients, 19 of whom were rolled over from our natural history study (The sample size was determined by the number of patients who were rolled over from Study 250-901 into Study 250-201. On the basis of the natural history data for untreated patients with MPS IIIA, 10 points of yearly decline in cognitive DQ score was assumed for the natural course of MPS IIIB, and the SD of the difference in yearly decline between pre- and post-treatment periods within a patient was assumed to be 10. Under these assumptions, a sample size of 20 patients was estimated to provide greater than 90% power to detect an 8-point difference in yearly decline between pre- and post-treatment periods, using a paired The primary objectives were to (a) evaluate the safety and tolerability of tralesinidase alfa administered to patients with MPS IIIB via an implanted i.c.v. reservoir and catheter, and (b) evaluate the impact of tralesinidase alfa on cognitive function as assessed by the DQ. Additional objectives were to (a) evaluate the impact of tralesinidase alfa on cognitive function as assessed by AEq score; (b) characterize the PK of tralesinidase alfa in CSF and plasma; (c) characterize the immunogenicity of tralesinidase alfa in CSF and serum; (d) evaluate the impact of tralesinidase alfa treatment on CSF, serum, and urine GAGs; and (e) evaluate the impact of tralesinidase alfa treatment on brain structure, liver size, and spleen size as assessed by MRI. | PMC9843052 | |
Inclusion and exclusion criteria. | All study participants had deficient NAGLU enzyme activity and | PMC9843052 | ||
Cognition. | Cognitive function was measured using the nonverbal scales of the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III) (The BSID-III is a validated and standardized developmental tool comprising 5 domains (cognitive, language, motor, social-emotional, and adaptive functioning) intended to assess developmental function in children ages 1 to 42 months (The KABC-II is a validated and standardized clinical psychological diagnostic test for assessing cognitive development (BSID-III or the KABC-II assessments were performed every 12 weeks in Study 250-201. Baseline, week 24, and week 48 visits involved 2 days of testing, with the cognitive, adaptive, and behavioral testing occurring on the first day (morning preferred), and MRI, lumbar puncture, and laboratory testing occurring on the second day to avoid confounding effects of sedation or general anesthetic administration. | PMC9843052 | ||
MRI assessments. | LIVER, BRAIN | Head and abdominal MRIs were used to assess regional brain, liver, and spleen volumes at baseline, week 24, and week 48 of Study 250-201. Brain volumetric analysis was performed on 3D T1-weighted images using the FreeSurfer Image Analysis Suite, version 5.3 (Martinos Center, Harvard University) (Brain volumes are noted without normalization, similarly to previous publications (Liver and spleen volumes were calculated by ICON Laboratory Services. Because liver and spleen volumes increased linearly compared with both age and BSA, these volumes were normalized to BSA, calculated using the Mosteller formula to allow for comparison among patients ranging from 2–9 years of age ( | PMC9843052 | |
Laboratory testing. | Tralesinidase alfa quantification in CSF and K2EDTA plasma was based on an electrochemiluminescence immunoassay (ECLA) technique using standard-bind, 96-well Meso Scale Discovery (MSD) streptavidin-coated plates. Samples were collected before dosing and 0.5, 4, 10, 24, 48, 72, 96, and 168 hours after drug administration at weeks 1 (baseline), 5, 12, and 36 of Study 250-201 Part 2. CSF samples were collected from the lateral ventricle through the i.c.v. port. Methods were validated, and sample analysis was conducted by Charles River laboratories.ADAs were measured in the CSF and serum using an ECLA method with MSD technology. Samples were diluted in a Master Mix with an equal concentration of ruthenylated (sulfo-tagged) tralesinidase alfa and biotinylated tralesinidase in the wells of polypropylene plates. Detection of ADAs is based on the bivalent characteristics of the antibodies; ADAs bind to both sulfo-tagged and biotinylated molecules to form an antibody complex bridge. Samples are dispensed onto streptavidin-coated MSD assay plates to allow binding of biotinylated tralesinidase alfa to the streptavidin in the wells. Only the samples that contain ADAs bound to both the biotinylated and sulfo-tagged tralesinidase alfa generate an ECL signal. In the presence of tripropylamine, ruthenium produces a chemiluminescent signal that is triggered when voltage is applied. The signal produced is proportional to the amount of ADAs present. Endpoint titer determination estimates the relative levels of ADAs for those positive samples. ADA assays were validated and samples were run by ICON Laboratory Services.Neutralizing antibodies were quantified in CSF using a cell-based assay that measured the ability of ADAs to interfere on CI-MPR–mediated uptake of tralesinidase alfa by the human Jurkat cell line. Tralesinidase alfa conjugated to Alexa 647 was monitored and quantified by flow cytometry using median fluorescence intensity (MFI) as the readout. The method was validated and samples were analyzed by Eurofins Pharma Bioanalytics Services US.Levels of tralesinidase alfa–specific IgE were quantified using tralesinidase alfa covalently coupled to ImmunoCAP. After washing away nonspecific IgE, a β-gal–labeled mouse monoclonal antibody against human IgE was added to form a complex. After incubation, unbound enzyme anti-IgE was washed away, and the bound complex was incubated with the ImmunoCAP Development Solution containing 4-methylumbelliferyl-β-Total HS and HS-NRE measurements in CSF and plasma were performed by ARUP Laboratories using a previously described method ( | PMC9843052 | ||
Statistical analysis. | No corrections or carry-forwards were made for missing values. A 2-tailed, paired | PMC9843052 | ||
Study approval. | Written informed consent from a parent or legal guardian and assent from the participant, if required, was obtained prior to conducting any study-specific assessments. This study was approved by the IRB affiliated with each individual clinical site: Children’s Hospital Oakland, Oakland, California, USA; Mackay Memorial Hospital-Taipei Branch, Taipei City, Taiwan; Great Ormond Street Hospital for Children NHS Foundation Trust – Great Ormond Street Hospital, London, United Kingdom; Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg, Germany; Fundación Cardio Infantil – Instituto de Cardiología, Bogotá, Colombia; Complexo Hospitalario Universitario de Santiago (CHUS) – Hospital Clínico Universitario, Santiago de Compostela, Spain; and Gazi Üniversitesi Tıp Fakültesi, Cocuk Sagligi ve Hastaliklari AD, Cocuk Beslenme ve Metabolizma ve Çocuk Genetik Hastaliklari BD, Gazi, Ankara, Turkey. | PMC9843052 | ||
Author contributions | AJS and SMM designed the clinical protocol. NM, AK, KVC, IO, FE, PH, MJDCL, MLC, SPL, SB, MC, and MS recruited participants and performed and supervised clinical practices. IN designed and performed the brain MRI analysis. B Kuca supervised the clinical study execution and was responsible for regulatory submissions. EZ, JK, and B Kaufman performed the data analysis. EZ and JK designed the data analysis and wrote the original draft of the manuscript. All authors reviewed and edited the manuscript. | PMC9843052 | ||
Supplementary Material | PMC9843052 | |||
Supplemental data | PMC9843052 | |||
Trial reporting checklists | PMC9843052 |
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