Introduction: C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited... Show moreIntroduction: C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited treatment options. Targeted inhibition of proximal AP through factor D (FD) blockade represents a rational treatment approach. We present two phase 2 proof-of-concept clinical studies of the orally active FD inhibitor danicopan in patients with C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) (NCT03369236 and NCT03459443). Methods: A double-blind, placebo-controlled study in patients with C3G and a single-arm, open-label study in patients with C3G or IC-MPGN treated with danicopan are reported. The studies evaluated pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety outcomes. The co-primary endpoints were change from baseline in composite biopsy score and the proportion of patients with a 30% reduction in proteinuria relative to baseline at 6 or 12 months. Results: Optimal systemic concentrations of danicopan were not achieved for complete and sustained inhibition of AP, although there was evidence that blockade of FD reduced AP activity shortly after drug administration. Consequently, limited clinical response was observed in key efficacy endpoints. While stable disease or improvement from baseline was seen in some patients, response was not consistent. The data confirmed the favorable safety profile of danicopan. Conclusion: While demonstrating a favorable safety profile, danicopan resulted in incomplete and inadequately sustained inhibition of AP, probably due to limitations in its PK/PD profile in C3G, leading to lack of efficacy. Complete and sustained AP inhibition is required for a clinical response in patients with C3G. Show less
Schaik, M. van; Arends, E.J.; Soonawala, D.; Ommen, E. van; Leeuw, K. de; Limper, M.; ... ; Teng, Y.K.O. 2022
Background: Belimumab, an anti-B-cell activating factor antibody, is approved for the treatment of auto-antibody positive systemic lupus erythematosus with a high degree of disease activity. Anti... Show moreBackground: Belimumab, an anti-B-cell activating factor antibody, is approved for the treatment of auto-antibody positive systemic lupus erythematosus with a high degree of disease activity. Anti-CD20 B cell depletion with rituximab is used in refractory SLE as well, although with variable responses. We hypothesized that incomplete B cell depletion, related to a surge in BAFF levels following rituximab treatment, can cause ongoing disease activity and flares. The Synbiose 1 study primarily focused on immunological effects and shows the preliminary clinical benefit of combined rituximab and belimumab in SLE. The Synbiose 2 study will evaluate the clinical efficacy of combining belimumab with rituximab in patients with severe SLE, allowing the tapering of prednisolone and mycophenolate. Methods: Synbiose 2 is a phase 3, multicenter, randomized, controlled, open-label 2-year clinical trial. Seventy adults with severe SLE including lupus nephritis will be randomized 1:1 to receive either standard of care consisting of prednisolone and mycophenolate as induction and maintenance treatment, or belimumab and rituximab combined with standard of care as induction treatment, followed by prednisolone and belimumab as maintenance treatment. The primary objective is to assess whether combined B cell therapy will lead to a reduction of treatment failure. Secondary endpoints are complete and partial clinical and renal response and the improvement of SLE-specific autoimmune phenomena. Safety endpoints include the incidence of adverse events, with a special interest in infections. Discussion: The Synbiose 2 trial is the first multicenter phase 3 clinical trial investigating combined B cell targeted therapy in SLE, including lupus nephritis. The outcome of this study will provide further evidence for the clinical efficacy of this new treatment strategy in severe SLE. Show less
This thesis focusses on the further unravelling of one of the mechanisms involved in developing Parkinson's disease: the GBA1 gene, encoding the lysosomal enzyme GCase. Several questions are... Show moreThis thesis focusses on the further unravelling of one of the mechanisms involved in developing Parkinson's disease: the GBA1 gene, encoding the lysosomal enzyme GCase. Several questions are addressed: How prevalent are mutations in this gene in the Netherlands and does it affect disease onset (chapter 2 and 5)? What methodological challenges accompany the sequencing of this gene (chapter 3 and 4)? What biomarkers may be used in clinical trials targeting GCase (chapter 6)? And what are the effects of the novel GCase activator LTI-291, when first administered to healthy volunteers (chapter 7) and to GBA-PD patients (chapter 8)? Show less
Objectives Recruiting general practitioners (GPs) and their multimorbid older patients for trials is challenging for multiple reasons (e.g., high workload, limited mobility). The comparability of... Show moreObjectives Recruiting general practitioners (GPs) and their multimorbid older patients for trials is challenging for multiple reasons (e.g., high workload, limited mobility). The comparability of study participants is important for interpreting study findings. This manuscript describes the baseline characteristics of GPs and patients participating in the 'Optimizing PharmacoTherapy in older multimorbid adults In primary CAre' (OPTICA) trial, a study of optimization of pharmacotherapy for multimorbid older adults. The overall aim of this study was to determine if the GPs and patients participating in the OPTICA trial are comparable to the real-world population in Swiss primary care. Design Analysis of baseline data from GPs and patients in the OPTICA trial and a reference cohort from the FIRE ('Family medicine ICPC Research using Electronic medical records') project. Setting Primary care, Switzerland. Participants Three hundred twenty-three multimorbid (>= 3 chronic conditions) patients with polypharmacy (>= 5 regular medications) aged >= 65 years and 43 GPs recruited for the OPTICA trial were compared to 22,907 older multimorbid patients with polypharmacy and 227 GPs from the FIRE database. Methods We compared the characteristics of GPs and patients participating in the OPTICA trial with other GPs and other older multimorbid adults with polypharmacy in the FIRE database. We described the baseline willingness to have medications deprescribed of the patients participating in the OPTICA trial using the revised Patients' Attitudes Towards Deprescribing (rPATD) questionnaire. Results The GPs in the FIRE project and OPTICA were similar in terms of sociodemographic characteristics and their work as a GP (e.g. aged in their fifties, >= 10 years of experience, >= 60% are self-employed, >= 80% work in a group practice). The median age of patients in the OPTICA trial was 77 years and 45% of trial participants were women. Patients participating in the OPTICA trial and patients in the FIRE database were comparable in terms of age, certain clinical characteristics (e.g. systolic blood pressure, body mass index) and health services use (e.g. selected lab and vital data measurements). More than 80% of older multimorbid patients reported to be willing to stop >= 1 of their medications if their doctor said that this would be possible. Conclusion The characteristics of patients and GPs recruited into the OPTICA trial are relatively comparable to characteristics of a real-world Swiss population, which indicates that recruiting a generalizable patient sample is possible in the primary care setting. Multimorbid patients in the OPTICA trial reported a high willingness to have medications deprescribed. Show less
A type I immune response is crucial for adequate tumor eradication by the immune system. However, tumors often gain evasion mechanisms that create barriers to the generation or effectiveness of a... Show moreA type I immune response is crucial for adequate tumor eradication by the immune system. However, tumors often gain evasion mechanisms that create barriers to the generation or effectiveness of a type I immune response. Among these barriers is the suppression of effective T cell priming and the inhibition of proper T cell infiltration and function in tumors. At present, the only therapies to target these barriers are focused on direct inhibition of T cell function by the tumor, through checkpoint molecules. These therapies are thus dependent on an existing type I response, and are generally not successful when tumors have insufficient T cells primed or infiltrated. This thesis has revealed ways to improve T cell priming and the infiltration of T cells in tumors. Show less
Existing quantitative imaging biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before... Show moreExisting quantitative imaging biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before incorporation into clinical trials. In radiomics, novel data-driven processes extract numerous visually imperceptible statistical features from the imaging data with no a priori assumptions on their correlation with biological processes. The selection of relevant features (radiomic signature) and incorporation into clinical trials therefore requires additional considerations to ensure meaningful imaging endpoints. Also, the number of radiomic features tested means that power calculations would result in sample sizes impossible to achieve within clinical trials. This article examines how the process of standardising and validating data-driven imaging biomarkers differs from those based on biological associations. Radiomic signatures are best developed initially on datasets that represent diversity of acquisition protocols as well as diversity of disease and of normal findings, rather than within clinical trials with standardised and optimised protocols as this would risk the selection of radiomic features being linked to the imaging process rather than the pathology. Normalisation through discretisation and feature harmonisation are essential pre-processing steps. Biological correlation may be performed after the technical and clinical validity of a radiomic signature is established, but is not mandatory. Feature selection may be part of discovery within a radiomics-specific trial or represent exploratory endpoints within an established trial; a previously validated radiomic signature may even be used as a primary/secondary endpoint, particularly if associations are demonstrated with specific biological processes and pathways being targeted within clinical trials. Show less
Background Acidosis-induced kidney injury is mediated by the intrarenal renin-angiotensin system, for which urinary renin is a potential marker. Therefore, we hypothesized that sodium bicarbonate... Show moreBackground Acidosis-induced kidney injury is mediated by the intrarenal renin-angiotensin system, for which urinary renin is a potential marker. Therefore, we hypothesized that sodium bicarbonate supplementation reduces urinary renin excretion in patients with chronic kidney disease (CKD) and metabolic acidosis.Methods Patients with CKD stage G4 and plasma bicarbonate 15-24 mmol/l were randomized to receive sodium bicarbonate (3 x 1000 mg/day, similar to 0.5 mEq/kg), sodium chloride (2 x 1,00 mg/day), or no treatment for 4 weeks (n = 15/arm). The effects on urinary renin excretion (primary outcome), other plasma and urine parameters of the renin-angiotensin system, endothelin-1, and proteinuria were analyzed.Results Forty-five patients were included (62 +/- 15 years, eGFR 21 +/- 5 ml/min/1.73m(2), plasma bicarbonate 21.7 +/- 3.3 mmol/l). Sodium bicarbonate supplementation increased plasma bicarbonate (20.8 to 23.8 mmol/l) and reduced urinary ammonium excretion (15 to 8 mmol/day, both P < 0.05). Furthermore, a trend towards lower plasma aldosterone (291 to 204 ng/L, P = 0.07) and potassium (5.1 to 4.8 mmol/l, P = 0.06) was observed in patients receiving sodium bicarbonate. Sodium bicarbonate did not significantly change the urinary excretion of renin, angiotensinogen, aldosterone, endothelin-1, albumin, or alpha 1-microglobulin. Sodium chloride supplementation reduced plasma renin (166 to 122 ng/L), and increased the urinary excretions of angiotensinogen, albumin, and alpha 1-microglobulin (all P < 0.05).Conclusions Despite correction of acidosis and reduction in urinary ammonium excretion, sodium bicarbonate supplementation did not improve urinary markers of the renin-angiotensin system, endothelin-1, or proteinuria. Possible explanations include bicarbonate dose, short treatment time, or the inability of urinary renin to reflect intrarenal renin-angiotensin system activity. Show less
BackgroundSchistosoma antigen detection in urine is a valuable diagnostic approach for schistosomiasis control programmes because of the higher sensitivity compared to parasitological methods and... Show moreBackgroundSchistosoma antigen detection in urine is a valuable diagnostic approach for schistosomiasis control programmes because of the higher sensitivity compared to parasitological methods and preferred sampling of urine over stool. Highly accurate diagnostics are important in low Schistosoma transmission areas. Pregnant women and young children could particularly benefit from antigen testing as praziquantel (PZQ) can be given to only confirmed Schistosoma cases. This prevents the unborn baby from unnecessary exposure to PZQ. We present here the protocol of a diagnostic study that forms part of the freeBILy project. The aim is to evaluate the accuracy of circulating anodic antigen (CAA) detection for diagnosis of Schistosoma haematobium infections in pregnant women and to validate CAA as an endpoint measure for anti-Schistosoma drug efficacy. The study will also investigate Schistosoma infections in infants.MethodsA set of three interlinked prospective, observational studies is conducted in Gabon. The upconverting phosphor lateral flow (UCP-LF) CAA test is the index diagnostic test that will be evaluated. The core trial, sub-study A, comprehensively evaluates the accuracy of the UCP-LF CAA urine test against a set of other Schistosoma diagnostics in a cross-sectional trial design. Women positive for S. haematobium will proceed with sub-study B and will be randomised to receive PZQ treatment immediately or after delivery followed by weekly sample collection. This approach includes comparative monitoring of CAA levels following PZQ intake and will also contribute further data for safety of PZQ administration during pregnancy. Sub-study C is a longitudinal study to determine the incidence of S. haematobium infection as well as the age for first infection in life-time.DiscussionThe freeBILy trial in Gabon will generate a comprehensive set of data on the accuracy of the UCP-LF CAA test for the detection of S. haematobium infection in pregnant women and newborn babies and for the use of CAA as a marker to determine PZQ efficacy. Furthermore, incidence of Schistosoma infection in infants will be reported. Using the ultrasensitive diagnostics, this information will be highly relevant for Schistosoma prevalence monitoring by national control programs as well as for the development of medicaments and vaccines.Trial registrationThe registration number of this study is NCT03779347 (clinicaltrials.gov, date of registration: 19 December 2018). Show less
Pharmacogenomics (PGx) utilizes an individual’s germline genetic profile to identify those who are at higher risk for ADRs or lack of efficacy. This information can be used by healthcare... Show morePharmacogenomics (PGx) utilizes an individual’s germline genetic profile to identify those who are at higher risk for ADRs or lack of efficacy. This information can be used by healthcare professionals (HCPs) to guide dose and drug selection before drug initiation in an effort to optimize drug therapy through precision medicine. Despite both the promise of and the progress in the field of PGx to achieve precision medicine, it is still not routinely applied in patient care. As such, a number of barriers preventing implementation have been identified. These include the undetermined model for delivering PGx, the lack of evidence supporting a PGx panel approach and the lack of tools supporting implementation. Therefore, the work of this thesis aims to support the implementation of precision medicine using PGx panel testing. It reports on generating evidence for PGx panel testing (Part I) and the development of tools facilitating implementation (Part II), evaluates the implementation process utilizing these tools (Part III) and quantifies the impact of PGx implementation on patient outcomes and cost-effectiveness (Part IV). Show less
Willmann, R.; Lee, J.; Turner, C.; Nagaraju, K.; Aartsma-Rus, A.; Wells, D.J.; ... ; Luca, A. de 2020
Clinical trials for rare neuromuscular diseases imply, among other investments, a high emotional burden for the whole disease community. Translation of data from preclinical studies to justify any... Show moreClinical trials for rare neuromuscular diseases imply, among other investments, a high emotional burden for the whole disease community. Translation of data from preclinical studies to justify any clinical trial must be carefully pondered in order to minimize the risk of clinical trial withdrawal or failure. A rigorous distinction between proofof-concept and preclinical efficacy studies using animal models is key to support the rationale of a clinical trial involving patients. This Review evaluates the experience accumulated by the TREAT-NMD Advisory Committee for Therapeutics, which provides detailed constructive feedback on clinical proposals for neuromuscular diseases submitted by researchers in both academia and industry, and emphasizes that a timely critical review of preclinical efficacy data from animal models, including biomarkers for specific diseases, combined with adherence to existing guidelines and standard protocols, can significantly help to de-risk clinical programs and prevent disappointments and costly engagement. Show less
Diks, A.M.; Bonroy, C.; Teodosio, C.; Groenland, R.J.; Mooij, B. de; Maertelaere, E. de; ... ; Berkowska, M.A. 2019
Obtaining reliable and reproducible high quality data in multicenter clinical research settings requires design of optimal standard operating procedures. While the need for standardization in... Show moreObtaining reliable and reproducible high quality data in multicenter clinical research settings requires design of optimal standard operating procedures. While the need for standardization in sample processing and data analysis is well-recognized, the impact of sample handling in the pre-analytical phase remains underestimated. We evaluated the impact of sample storage time (approximate to transport time) and temperature, type of anticoagulant, and limited blood volume on reproducibility of flow cytometric studies.EDTA and Na-Heparin samples processed with the EuroFlow bulk lysis protocol, stained and stored at 4 degrees C showed fairly stable expression of cell surface markers and distribution of the major leukocyte populations for up to 72 h. Additional sample fixation (1% PFA, Fix & Perm) did not have any beneficial effects. Blood samples stored for < 24 h at room temperature before processing and staining seemed suitable for reliable immunophenotyping, although losses in absolute cell numbers were observed. The major losses were observed in myeloid cells and monocytes, while lymphocytes seemed less affected. Expression of cell surface markers and population distribution were more stable in Na-Heparin blood than in EDTA blood. However, storage of Na-Heparin samples was associated with faster decrease in leukocyte counts over time. Whole blood fixation strategies (Cyto-Chex, TransFix) improved long-term population distribution, but were detrimental for expression of cellular markers. The main conclusions from this study on healthy donor blood samples were successfully confirmed in EDTA clinical (patient) blood samples with different time delays until processing. Finally, we recognized the need for adjustments in bulk lysis in case of insufficient blood volumes.Despite clear overall conclusions, individual markers and cell populations had different preferred conditions. Therefore, specific guidelines for sample handling should always be adjusted to the clinical application and the main target leukocyte population. Show less
In this thesis we describe the latest developments in the field of advanced thyroid cancer. Several clinical trials with sorafenib and everolimus were performed. The relation between clinical... Show moreIn this thesis we describe the latest developments in the field of advanced thyroid cancer. Several clinical trials with sorafenib and everolimus were performed. The relation between clinical outcome and mutational status was analyzed. Furthermore, the pharmacokinetics of everolimus in patients with advanced thyroid cancer was described. Show less
