BACKGROUND. Antigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen... Show moreBACKGROUND. Antigen-specific regulation of autoimmune disease is a major goal. In seropositive rheumatoid arthritis (RA), T cell help to autoreactive B cells matures the citrullinated (Cit) antigen-specific immune response, generating RA-specific V domain glycosylated anti-Cit protein antibodies (ACPA VDG) before arthritis onset. Low or escalating antigen administration under "sub-immunogenic" conditions favors tolerance. We explored safety, pharmacokinetics, and immunological and clinical effects of s.c. DEN-181, comprising liposomes encapsulating self-peptide collagen II259-273(CII) and NF-KB inhibitor 1,25-dihydroxycholecalciferol.METHODS. A double-blind, placebo-controlled, exploratory, single-ascending-dose, phase I trial assessed the impact of low, medium, and high DEN-181 doses on peripheral blood CII-specific and bystander Cit64vimentin59-71-specific (Cit-Vim-specific) autoreactive T cell responses, cytokines, and ACPA in 17 HLA-DRB1*04:01+ or *01:01+ ACPA+ RA patients on methotrexate. RESULTS. DEN-181 was well tolerated. Relative to placebo and normalized to baseline values, Cit-Vim-specific T cells decreased in patients administered medium and high doses of DEN-181. Relative to placebo, percentage of CII-specific programmed cell death 1+ T cells increased within 28 days of DEN-181. Exploratory analysis in DEN-181-treated patients suggested improved RA disease activity was associated with expansion of CII-specific and Cit-Vim-specific T cells; reduction in ACPA VDG, memory B cells, and inflammatory myeloid populations; and enrichment in CCR7+ and naive T cells. Single-cell sequencing identified T cell transcripts associated with tolerogenic TCR signaling and exhaustion after low or medium doses of DEN-181.CONCLUSION. The safety and immunomodulatory activity of low/medium DEN-181 doses provide rationale to further assess antigen-specific immunomodulatory therapy in ACPA+ RA.TRIAL REGISTRATION. Anzctr.org.au identifier ACTRN12617001482358, updated September 8, 2022.FUNDING. Innovative Medicines Initiative 2 Joint Undertaking (grant agreement 777357), supported by European Union's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations; Arthritis Queensland; National Health and Medical Research Council (NHMRC) Senior Research Fellowship; and NHMRC grant 2008287. Show less
Background Digital biomarkers are a promising novel method to capture clinical data in a home setting. However, clinical validation prior to implementation is of vital importance. The aim of this... Show moreBackground Digital biomarkers are a promising novel method to capture clinical data in a home setting. However, clinical validation prior to implementation is of vital importance. The aim of this study was to clinically validate physical activity, heart rate, sleep and forced expiratory volume in 1 s (FEV1) as digital biomarkers measured by a smartwatch and portable spirometer in children with asthma and cystic fibrosis (CF). Methods This was a prospective cohort study including 60 children with asthma and 30 children with CF (aged 6-16 years). Participants wore a smartwatch, performed daily spirometry at home and completed a daily symptom questionnaire for 28 days. Physical activity, heart rate, sleep and FEV1 were considered candidate digital end-points. Data from 128 healthy children were used for comparison. Reported outcomes were compliance, difference between patients and controls, correlation with disease activity, and potential to detect clinical events. Analysis was performed with linear mixed effects models. Results Median compliance was 88%. On average, patients exhibited lower physical activity and FEV1 compared with healthy children, whereas the heart rate of children with asthma was higher compared with healthy children. Days with a higher symptom score were associated with lower physical activity for children with uncontrolled asthma and CF. Furthermore, FEV1 was lower and (nocturnal) heart rate was higher for both patient groups on days with more symptoms. Candidate biomarkers appeared able to describe a pulmonary exacerbation. Conclusions Portable spirometer- and smartwatch-derived digital biomarkers show promise as candidate end-points for use in clinical trials or clinical care in paediatric lung disease. Show less
Dijkstra, F.M.; Loo, A.J. van de; Abdulahad, S.; Bosma, E.R.; Hartog, M.; Huls, H.; ... ; Verster, J.C. 2022
Background: Intranasal esketamine demonstrates rapid improvement of depressive symptoms. However, transient adverse effects (dissociation, sedation and dizziness) may occur, which could impact... Show moreBackground: Intranasal esketamine demonstrates rapid improvement of depressive symptoms. However, transient adverse effects (dissociation, sedation and dizziness) may occur, which could impact driving performance. Aims: To evaluate the effects of 84 mg intranasal esketamine on driving performance in unipolar major depressive disorder (MDD) or persistent depressive disorder (PDD) patients. Methods: The study consisted of two parts. Part A was a single-blind, double-dummy, randomized three-period, cross-over study to compare effects of esketamine versus placebo on next morning driving, 18 +/- 2 h post-treatment. Alcohol was administered to demonstrate assay sensitivity. In Part B, same-day driving, 6 +/- 0.5 hours post-treatment, was assessed during twice weekly esketamine administration for 3 weeks. Twenty-seven patients with mild-to-moderate MDD or PDD without psychotic features completed a 100 km on-the-road driving test on a public highway in normal traffic. The primary outcome was standard deviation of lateral position (SDLP; cm; weaving of car). Results: In Part A, alcohol impaired driving performance compared to placebo: Least-square means (95% CI), p-value for delta SDLP (cm) compared with placebo: (Delta SDLP = + 1.83 (1.03; 2.62), p < 0.001), whereas esketamine did not: (Delta SDLP = -0.23 (-1.04; 0.58), p = 0.572). In Part B, weekly driving tests showed no differences between placebo baseline SDLP and after esketamine administration over 3 weeks: Day 11: (Delta SDLP = -0.96 (-3.72; 1.81), p = 0.493), Day 18: (Delta SDLP = -0.56 (-3.33; 2.20), p = 0.686) and Day 25: (Delta SDLP = -1.05 (-3.82; 1.71), p = 0.451). Conclusions: In this study, esketamine did not impair on-road driving performance the next morning following a single dose, or on same day after repeated administration. Show less
IntroductionCoughing is a common symptom in pediatric lung disease and cough frequency has been shown to be correlated to disease activity in several conditions. Automated cough detection could... Show moreIntroductionCoughing is a common symptom in pediatric lung disease and cough frequency has been shown to be correlated to disease activity in several conditions. Automated cough detection could provide a noninvasive digital biomarker for pediatric clinical trials or care. The aim of this study was to develop a smartphone-based algorithm that objectively and automatically counts cough sounds of children.MethodsThe training set was composed of 3228 pediatric cough sounds and 480,780 noncough sounds from various publicly available sources and continuous sound recordings of 7 patients admitted due to respiratory disease. A Gradient Boost Classifier was fitted on the training data, which was subsequently validated on recordings from 14 additional patients aged 0–14 admitted to the pediatric ward due to respiratory disease. The robustness of the algorithm was investigated by repeatedly classifying a recording with the smartphone-based algorithm during various conditions.ResultsThe final algorithm obtained an accuracy of 99.7%, sensitivity of 47.6%, specificity of 99.96%, positive predictive value of 82.2% and negative predictive value 99.8% in the validation dataset. The correlation coefficient between manual- and automated cough counts in the validation dataset was 0.97 (p < .001). The intra- and interdevice reliability of the algorithm was adequate, and the algorithm performed best at an unobstructed distance of 0.5–1 m from the audio source.ConclusionThis novel smartphone-based pediatric cough detection application can be used for longitudinal follow-up in clinical care or as digital endpoint in clinical trials. Show less
Vrouwe, J.P.M.; Kamerling, I.M.C.; Esdonk, M.J. van; Metselaar, J.M.; Stuurman, F.E.; Pluijm, G. van der; ... ; Osanto, S. 2021
Dexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome-encapsulated dexamethasone disodium phosphate ... Show moreDexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome-encapsulated dexamethasone disodium phosphate (liposomal dexamethasone) administration in mCRPC patients. In this exploratory first-in-man study, patients in part A received a starting dose of 10 mg followed by five doses of 20 mg liposomal dexamethasone at 2-week intervals. Upon review of part A safety, patients in part B received 10 weekly doses of 18.5 mg. Primary outcomes were safety and pharmacokinetic profile, secondary outcome was antitumor efficacy. Nine mCRPC patients (5 part A, 4 part B) were enrolled. All patients experienced grade 1-2 toxicity, one (part B) patient experienced grade 3 toxicity (permanent bladder catheter-related urosepsis). No infusion-related adverse events occurred. One patient had upsloping glucose levels <= 9.1 mmol/L. Trough plasma concentrations of liposomal- and free dexamethasone were below the lower limit of quantification (LLOQ) in part A, and above LLOQ in three patients in part B (t(1/2) similar to 50 h for liposomal dexamethasone), trough concentrations of liposomal- and free dexamethasone increased toward the end of the study. In seven of nine patients (78%) patients, stable disease was observed in bone and/or CT scans at follow-up, and in one (part B) of these seven patients a >50% PSA biochemical response was observed. Bi- and once weekly administrations of IV liposomal dexamethasone were well-tolerated. Weekly dosing enabled trough concentrations of liposomal- and free dexamethasone >LLOQ. The data presented support further clinical investigation in well-powered studies. Clinical trial registration: ISRCTN 10011715. Show less
Introduction: The duration and frequency of crying of an infant can be indicative of its health. Manual tracking and labeling of crying is laborious, subjective, and sometimes inaccurate. The aim... Show moreIntroduction: The duration and frequency of crying of an infant can be indicative of its health. Manual tracking and labeling of crying is laborious, subjective, and sometimes inaccurate. The aim of this study was to develop and technically validate a smartphone-based algorithm able to automatically detect crying.Methods: For the development of the algorithm a training dataset containing 897 5-s clips of crying infants and 1,263 clips of non-crying infants and common domestic sounds was assembled from various online sources. OpenSMILE software was used to extract 1,591 audio features per audio clip. A random forest classifying algorithm was fitted to identify crying from non-crying in each audio clip. For the validation of the algorithm, an independent dataset consisting of real-life recordings of 15 infants was used. A 29-min audio clip was analyzed repeatedly and under differing circumstances to determine the intra- and inter- device repeatability and robustness of the algorithm.Results: The algorithm obtained an accuracy of 94% in the training dataset and 99% in the validation dataset. The sensitivity in the validation dataset was 83%, with a specificity of 99% and a positive- and negative predictive value of 75 and 100%, respectively. Reliability of the algorithm appeared to be robust within- and across devices, and the performance was robust to distance from the sound source and barriers between the sound source and the microphone.Conclusion: The algorithm was accurate in detecting cry duration and was robust to various changes in ambient settings. Show less
Kruizinga, M.D.; Heide, N. van der; Moll, A.; ZhuParris, A.; Yavuz, Y.; Kam, M.L. de; ... ; Driessen, G.J.A. 2021
Background: Digital devices and wearables allow for the measurement of a wide range of health-related parameters in a non-invasive manner, which may be particularly valuable in pediatrics.... Show moreBackground: Digital devices and wearables allow for the measurement of a wide range of health-related parameters in a non-invasive manner, which may be particularly valuable in pediatrics. Incorporation of such parameters in clinical trials or care as digital endpoint could reduce the burden for children and their parents but requires clinical validation in the target population. This study aims to determine the tolerability, repeatability, and reference values of novel digital endpoints in healthy children.MethodsApparently healthy children (n = 175, 46% male) aged 2-16 were included. Subjects were monitored for 21 days using a home-monitoring platform with several devices (smartwatch, spirometer, thermometer, blood pressure monitor, scales). Endpoints were analyzed with a mixed effects model, assessing variables that explained within- and between-subject variability. Endpoints based on physical activity, heart rate, and sleep-related parameters were included in the analysis. For physical-activity-related endpoints, a sample size needed to detect a 15% increase was calculated.FindingsMedian compliance was 94%. Variability in each physical activity-related candidate endpoint was explained by age, sex, watch wear time, rain duration per day, average ambient temperature, and population density of the city of residence. Estimated sample sizes for candidate endpoints ranged from 33-110 per group. Daytime heart rate, nocturnal heart rate and sleep duration decreased as a function of age and were comparable to reference values published in the literature.ConclusionsWearable- and portable devices are tolerable for pediatric subjects. The raw data, models and reference values presented here can be used to guide further validation and, in the future, clinical trial designs involving the included measures. Show less
Novel digital endpoints gathered via wearables, small devices, or algorithms hold great promise for clinical trials. However, implementation has been slow because of a lack of guidelines regarding... Show moreNovel digital endpoints gathered via wearables, small devices, or algorithms hold great promise for clinical trials. However, implementation has been slow because of a lack of guidelines regarding the validation process of these new measurements. In this paper, we propose a pragmatic approach toward selection and fit-for-purpose validation of digital endpoints. Measurements should be value-based, meaning the measurements should directly measure or be associated with meaningful outcomes for patients. Devices should be assessed regarding technological validity. Most importantly, a rigorous clinical validation process should appraise the tolerability, difference between patients and controls, repeatability, detection of clinical events, and correlation with traditional endpoints. When technically and clinically fit-for-purpose, case building in interventional clinical trials starts to generate evidence regarding the response to new or existing health-care interventions. This process may lead to the digital endpoint replacing traditional endpoints, such as clinical rating scales or questionnaires in clinical trials. We recommend initiating more data-sharing collaborations to prevent unnecessary duplication of research and integration of value-based measurements in clinical care to enhance acceptance by health-care professionals. Finally, we invite researchers and regulators to adopt this approach to ensure a timely implementation of digital measurements and value-based thinking in clinical trial design and health care.Significance Statement-Novel digital endpoints are often cited as promising for the clinical trial of the future. However, clear validation guidelines are lacking in the literature. This paper contains pragmatic criteria for the selection, technical validation, and clinical validation of novel digital endpoints and provides recommendations for future work and collaboration. Show less
Background Diagnosis and follow-up of respiratory diseases traditionally rely on pulmonary function tests (PFTs), which are currently performed in hospitals and require trained personnel.... Show moreBackground Diagnosis and follow-up of respiratory diseases traditionally rely on pulmonary function tests (PFTs), which are currently performed in hospitals and require trained personnel. Smartphone-connected spirometers, like the Air Next spirometer, have been developed to aid in the home monitoring of patients with pulmonary disease. The aim of this study was to investigate the technical validity and usability of the Air Next spirometer in pediatric patients. Methods Device variability was tested with a calibrated syringe. About 90 subjects, aged 6 to 16, were included in a prospective cohort study. Fifty-eight subjects performed conventional spirometry and subsequent Air Next spirometry. The bias and the limits of agreement between the measurements were calculated. Furthermore, subjects used the device for 28 days at home and completed a subject-satisfaction questionnaire at the end of the study period. Results Interdevice variability was 2.8% and intradevice variability was 0.9%. The average difference between the Air Next and conventional spirometry was 40 mL for forced expiratory volume in 1 second (FEV1) and 3 mL for forced vital capacity (FVC). The limits of agreement were -270 mL and +352 mL for FEV1 and -403 mL and +397 mL for FVC. About 45% of FEV1 measurements and 41% of FVC measurements at home were acceptable and reproducible according to American Thoracic Society/European Respiratory Society criteria. Parents scored difficulty, usefulness, and reliability of the device 1.9, 3.5, and 3.8 out of 5, respectively. Conclusion The Air Next device shows validity for the measurement of FEV1 and FVC in a pediatric patient population. Show less
Purpose Recombinant human erythropoietin (rHuEPO) is known to increase thrombotic risk in patients and might have similar effects in athletes abusing the drug. rHuEPO is prohibited by anti-doping... Show morePurpose Recombinant human erythropoietin (rHuEPO) is known to increase thrombotic risk in patients and might have similar effects in athletes abusing the drug. rHuEPO is prohibited by anti-doping legislation, but this risk has not been investigated thoroughly. This analysis was designed to evaluate whether rHuEPO impacts hemostatic profile and endothelial and platelet activation markers in trained subjects, and whether the combination with exercise affects exercise induced alterations. Methods This double-blind, randomized, placebo-controlled trial enrolled healthy, trained male cyclists aged 18-50 years. Participants were randomly allocated (1:1) to receive subcutaneous injections of rHuEPO (epoetin-beta; mean dose 6000 IU per week) or placebo (0.9% NaCl) for 8 weeks. Subjects performed five maximal exercise tests and a road race, coagulation and endothelial/platelet markers were measured at rest and directly after each exercise effort. Results rHuEPO increased P-selectin (+ 7.8% (1.5-14.5),p = 0.02) and E-selectin (+ 8.6% (2.0-15.7),p = 0.01) levels at rest. Maximal exercise tests significantly influenced all measured coagulation and endothelial/platelet markers, and in the rHuEPO group maximal exercise tests led to 15.3% ((7.0-24.3%),p = 0.0004) higher E-selectin and 32.1% ((4.6-66.8%),p = 0.0207) higher Platelet factor 4 (PF4) levels compared to the placebo group. Conclusion In conclusion, rHuEPO treatment resulted in elevated E- and P-selectin levels in trained cyclists, indicating enhanced endothelial activation and/or platelet reactivity. Exercise itself induces hypercoagulability, and the combination of rHuEPO and exercise increased E-selectin and PF4 levels more than either intervention alone. Based on this, exercise potentially increases thrombotic risk, a risk that might be enhanced in combination with rHuEPO use. Show less
Veld, A.E.I.; Grievink, H.W.; Saghari, M.; Stuurman, F.E.; Kam, M.L. de; Vries, A.P.J. de; ... ; Moerland, M. 2019
Recombinant human erythropoietin (rHuEPO) is used as doping a substance. Anti-doping efforts include urine and blood testing and monitoring the athlete biological passport (ABP). As data on the... Show moreRecombinant human erythropoietin (rHuEPO) is used as doping a substance. Anti-doping efforts include urine and blood testing and monitoring the athlete biological passport (ABP). As data on the performance of these methods are incomplete, this study aimed to evaluate the performance of two common urine assays and the ABP. In a randomized, double-blinded, placebo-controlled trial, 48 trained cyclists received a mean dose of 6000 IU rHuEPO (epoetin beta) or placebo by weekly injection for eight weeks. Seven timed urine and blood samples were collected per subject. Urine samples were analyzed by sarcosyl-PAGE and isoelectric focusing methods in the accredited DoCoLab in Ghent. A selection of samples, including any with false presumptive findings, underwent a second sarcosyl-PAGE confirmation analysis. Hematological parameters were used to construct a module similar to the ABP and analyzed by two evaluators from an Athlete Passport Management Unit. Sensitivity of the sarcosyl-PAGE and isoelectric focusing assays for the detection of erythropoietin abuse were 63.8% and 58.6%, respectively, with a false presumptive finding rate of 4.3% and 6%. None of the false presumptive findings tested positive in the confirmation analysis. Sensitivity was highest between 2 and 6 days after dosing, and dropped rapidly outside this window. Sensitivity of the ABP was 91.3%. Specificity of the urine assays was high; however, the detection window of rHuEPO was narrow, leading to questionable sensitivity. The ABP, integrating longitudinal data, is more sensitive, but there are still subjects that evade detection. Combining these methods might improve performance, but will not resolve all observed shortcomings. Show less
Context: A somatostatin-dopamine chimera (BIM23B065) was under investigation to reduce GH secretion for the treatment of pituitary adenomas.Objective: To determine pharmacokinetics, safety, and... Show moreContext: A somatostatin-dopamine chimera (BIM23B065) was under investigation to reduce GH secretion for the treatment of pituitary adenomas.Objective: To determine pharmacokinetics, safety, and tolerability and to monitor hormonal changes after single and multiple subcutaneous BIM23B065 administrations.Design: Randomized, double-blind, placebo-controlled, parallel-group design with five single and three 13-day multiple ascending-dose cohorts.Patients: A total of 63 healthy male white volunteers were enrolled (47 active, 16 placebo).Main Outcome Measures: Pharmacokinetics, GH, prolactin (PRL), IGF-1, GH after GHRH administration, and general clinical safety criteria.Results: The maximum dosage of BIM23B065 administered in this study was 1.5 mg. BIM23B065 reduced the mean GH concentrations after 8 and 13 days of treatment. A decrease in GH release after GHRH administration indicated inhibition of the hypothalamic-pituitary-somatotropic axis. IGF-1 was not altered after single doses but showed a significant change from baseline after multiple dosing. PRL secretion was reduced in all subjects who were treated. Orthostatic hypotension and injection site reactions were commonly observed at high dosages. A 6-day uptitration period was included to successfully lower the cardiovascular effects in the multiple ascending dose part of the study.Conclusions: Proof of pharmacology of BIM23B065 was shown by a reduction in GH, IGF-1, and PRL concentrations in healthy male volunteers, supporting activity of the somatostatin analog and dopamine agonist moieties. The safety and tolerability of the higher dosing regions was limited mainly by orthostatic hypotension. Show less
A somatostatin-dopamine chimera (BIM23B065) was under investigation to reduce growth hormone (GH) secretion for the treatment of pituitary adenomas.To determine the pharmacokinetics, safety,... Show moreA somatostatin-dopamine chimera (BIM23B065) was under investigation to reduce growth hormone (GH) secretion for the treatment of pituitary adenomas.To determine the pharmacokinetics, safety, tolerability, and to monitor hormonal changes after single and multiple subcutaneous BIM23B065 administrations.Randomized, double-blind, placebo-controlled, parallel-group design with five single and three 13-day multiple ascending dose cohorts.A total of 63 healthy male Caucasian volunteers were enrolled, 47 active, 16 placebo.Pharmacokinetics, GH, prolactin (PRL), insulin-like growth factor-1 (IGF-1), GH after GH releasing hormone (GHRH) administration, and general clinical safety criteria.The maximum dose administered of BIM23B065 in this study was 1.5 mg. BIM23B065 reduced the mean GH concentrations after 8 and 13 days of treatment. A decrease in GH release after GHRH administration indicated inhibition of the hypothalamus-pituitary-somatotropic axis. IGF-1 was not altered after single doses but showed a significant change from baseline after multiple dosing. The secretion of PRL was reduced in all treated subjects. Orthostatic hypotension and injection site reactions were commonly observed at high doses. A 6-day up-titration period was included to successfully lower the cardiovascular effects in the multiple ascending dose part of the study.Proof-of-pharmacology of BIM23B065 was shown by a reduction in GH, IGF-1 and PRL concentrations in healthy male volunteers, supportive for activity of the somatostatin analogue and dopamine agonist moieties. The safety and tolerability in the higher dosing regions was mainly limited by orthostatic hypotension.ContextObjectiveDesignPatientsMain Outcome MeasuresResultsConclusions Show less
Heuberger, J.A.A.C.; Rotmans, J.I.; Gal, P.; Stuurman, F.E.; Westende, J. van 't; Post, T.E.; ... ; Cohen, A.F. 2017
