Clinical trials
Abstract
BACKGROUND. Major depressive disorder (MDD) can benefit from novel interventions and personalization. Deep transcranial magnetic stimulation (Deep TMS) targeting the lateral prefrontal cortex (LPFC) using the H1 Coil, was FDA-cleared for treatment of MDD, however recent preliminary data indicate that targeting medial prefrontal cortex (MPFC) using the H7 Coil might induce as good or even better outcomes. Here we explored whether Deep TMS targeting the MPFC is non-inferior to targeting LPFC, and whether electrophysiological or clinical markers for patient selection can be identified. METHODS. The present prospective multicenter randomized study enrolled 169 MDD patients who failed antidepressant treatments in the current episode. Patients were randomized to receive 24 Deep TMS sessions over 6 weeks, using either the H1 Coil or the H7 Coil. The primary efficacy endpoint was the change from baseline to week 6 in the Hamilton-Depression-Rating-Scores. RESULTS. Clinical efficacy and safety profiles were similar and not significantly different between groups, with response rates of 60.9% for the H1 Coil and 64.2% for the H7 Coil. Moreover, brain activity measured by EEG during the first treatment session correlated with clinical outcomes in a coil-specific manner, and a cluster of baseline clinical symptoms was found to potentially distinguish between patients who can benefit from each Deep TMS target. CONCLUSION. This study provides a new treatment option for MDD, using the H7 Coil, and initial guidance to differentiate between patients likely to respond to LPFC versus MPFC stimulation targets, which require further validation studies. TRIAL REGISTRATION. ClinicalTrials.gov NCT03012724. FUNDING. Brainsway Ltd.
Authors
Abraham Zangen, Samuel Zibman, Aron Tendler, Noam Barnea-Ygael, Uri Alyagon, Daniel M. Blumberger, Geoffrey Grammer, Hadar Shalev, Tatiana Gulevsky, Tanya Vapnik, Alexander Bystritsky, Igor Filipčić, David Feifel, Ahava Stein, Frederic Deutsch, Yiftach Roth, Mark S. George
Abstract
BACKGROUND Adverse drug reactions are unpredictable immunologic events presenting frequent challenges to clinical management. Systemically administered cholecalciferol (vitamin D3) has immunomodulatory properties. In this randomized, double-blinded, placebo-controlled interventional trial of healthy human adults, we investigated the clinical and molecular immunomodulatory effects of a single high dose of oral vitamin D3 on an experimentally induced chemical rash.METHODS Skin inflammation was induced with topical nitrogen mustard (NM) in 28 participants. Participant-specific inflammatory responses to NM alone were characterized using clinical measures, serum studies, and skin tissue analysis over the next week. All participants underwent repeat NM exposure to the opposite arm and then received placebo or 200,000 IU cholecalciferol intervention. The complete rash reaction was followed by multi-omic analysis, clinical measures, and serum studies over 6 weeks.RESULTS Cholecalciferol mitigated acute inflammation in all participants and achieved 6 weeks of durable responses. Integrative analysis of skin and blood identified an unexpected divergence in response severity to NM, corroborated by systemic neutrophilia and significant histopathologic and clinical differences. Multi-omic and pathway analyses revealed a 3-biomarker signature (CCL20, CCL2, CXCL8) unique to exaggerated responders that is suppressed by cholecalciferol and implicates IL-17 signaling involvement.CONCLUSION High-dose systemic cholecalciferol may be an effective treatment for severe reactions to topical chemotherapy. Our findings have broad implications for cholecalciferol as an antiinflammatory intervention against the development of exaggerated immune responses.TRIAL REGISTRATION clinicaltrials.gov (NCT02968446).FUNDING NIH and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS; grants U01AR064144, U01AR071168, P30 AR075049, U54 AR079795, and P30 AR039750 (CWRU)).
Authors
Madison K. Ernst, Spencer T. Evans, Jose-Marc Techner, Robert M. Rothbaum, Luisa F. Christensen, Ummiye Venus Onay, Dauren Biyashev, Michael M. Demczuk, Cuong V. Nguyen, Kord S. Honda, Thomas S. McCormick, Lam C. Tsoi, Johann E. Gudjonsson, Kevin D. Cooper, Kurt Q. Lu
Abstract
BACKGROUND Primary Sjögren’s syndrome (pSS) is characterized by B cell hyperactivity and elevated B-lymphocyte stimulator (BLyS). Anti-BLyS treatment (e.g., belimumab) increases peripheral memory B cells; decreases naive, activated, and plasma B cell subsets; and increases stringency on B cell selection during reconstitution. Anti-CD20 therapeutics (e.g., rituximab) bind and deplete CD20-expressing B cells in circulation but are less effective in depleting tissue-resident CD20+ B cells. Combined, these 2 mechanisms may achieve synergistic effects.METHODS This 68-week, phase II, double-blind study (GSK study 201842) randomized 86 adult patients with active pSS to 1 of 4 arms: placebo, s.c. belimumab, i.v. rituximab, or sequential belimumab + rituximab.RESULTS Overall, 60 patients completed treatment and follow-up until week 68. The incidence of adverse events (AEs) and drug-related AEs was similar across groups. Infections/infestations were the most common AEs, and no serious infections of special interest occurred. Near-complete depletion of minor salivary gland CD20+ B cells and a greater and more sustained depletion of peripheral CD19+ B cells were observed with belimumab + rituximab versus monotherapies. With belimumab + rituximab, reconstitution of peripheral B cells occurred, but it was delayed compared with rituximab. At week 68, mean (± standard error) total EULAR Sjögren’s syndrome disease activity index scores decreased from 11.0 (1.17) at baseline to 5.0 (1.27) for belimumab + rituximab and 10.4 (1.36) to 8.6 (1.57) for placebo.CONCLUSION The safety profile of belimumab + rituximab in pSS was consistent with the monotherapies. Belimumab + rituximab induced enhanced salivary gland B cell depletion relative to the monotherapies, potentially leading to improved clinical outcomes.TRIAL REGISTRATION ClinicalTrials.gov NCT02631538.FUNDING Funding was provided by GSK.
Authors
Xavier Mariette, Francesca Barone, Chiara Baldini, Hendrika Bootsma, Kenneth L. Clark, Salvatore De Vita, David H. Gardner, Robert B. Henderson, Michael Herdman, Karoline Lerang, Prafull Mistry, Raj Punwaney, Raphaele Seror, John Stone, Paul L.A. van Daele, André van Maurik, Nicolas Wisniacki, David A. Roth, Paul Peter Tak
Abstract
The efficacy of abatacept in patients with early diffuse systemic sclerosis (dcSSc) was analyzed to test the hypothesis that patients in the inflammatory intrinsic gene expression subset would show the most significant clinical improvement. 84 participants with dcSSc were randomized to receive abatacept or placebo for 12 months. RNA-seq was performed on 233 skin paired biopsies at baseline, 3- and 6-months. Improvement was defined as a 5 point or >20% change in modified Rodnan skin score (mRSS) between baseline and 12 months. Samples were assigned to intrinsic gene expression subset (inflammatory, fibroproliferative, or normal-like). In the abatacept arm, change in mRSS was most pronounced for the inflammatory (p<0.001) and normal-like (p=0.03) subsets relative to placebo. Participants on placebo remained in their molecular subset while inflammatory participants treated with abatacept moved toward normal-like. The CD28 costimulation pathway decreased in patients that improved on abatacept (FDR=5.88x10-4) and was specific to the inflammatory subset (FDR=0%). Patients in the inflammatory subset had elevation of the CD28 costimulation pathway at baseline relative to fibroproliferative (p = 0.0026) and normal-like (p=0.0001) participants. There was a correlation between improved ΔmRSS and baseline expression of the CD28 costimulation pathway (R=-0.62, p=0.02). This study provides an example of precision medicine in SSc clinical trials.
Authors
Bhaven K. Mehta, Monica E. Espinoza, Jennifer M. Franks, Yiwei Yuan, Yue Wang, Tammara Wood, Johann Gudjonsson, Cathie Spino, David A. Fox, Dinesh Khanna, Michael L. Whitfield
Abstract
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-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-κB 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.
Authors
Amee Sonigra, Hendrik J. Nel, Pascale Wehr, Nishta Ramnoruth, Swati Patel, Karin A. van Schie, Maxwell W. Bladen, Ahmed M. Mehdi, Joanne Tesiram, Meghna Talekar, Jamie Rossjohn, Hugh H. Reid, Frederik E. Stuurman, Helen Roberts, Phillip Vecchio, Ian Gourley, Mark Rigby, Stephane Becart, Rene E.M. Toes, Hans Ulrich Scherer, Kim-Anh Lê Cao, Kim Campbell, Ranjeny Thomas
Abstract
BACKGROUND. Alcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 receptor agonist exenatide reduces alcohol consumption in rodents and non-human primates, but its efficacy in patients with AUD is unknown. METHODS. In a randomized, double-blinded, placebo-controlled clinical trial, treatment-seeking AUD patients were assigned to receive exenatide (2 mg subcutaneously) or placebo once weekly for 26-weeks, in addition to standard cognitive-behavioral therapy. The primary outcome was reduction in number of heavy drinking days. A subgroup also completed fMRI and SPECT brain scans. RESULTS. A total of 127 patients were enrolled. Our data revealed that although exenatide did not significantly reduce the number of heavy drinking days compared to placebo, it significantly attenuated fMRI alcohol cue-reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. In addition, the dopamine transporter availability was lower in the exenatide group compared to the placebo group. Exploratory analyses revealed that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients (BMI>30 kg/m2). Adverse events were mainly gastrointestinal. CONCLUSIONS. This first RCT on the effects of a GLP-1 receptor agonist in AUD provides new important knowledge on the effects of GLP-1 receptor agonists as a novel treatment target in addiction. TRIAL REGISTRATION. EudraCT: 2016-003343-11 and ClinicalTrials.gov: NCT03232112 FUNDING. The Novavi Foundation; The Research Foundation, Mental Health Services, Capital Region of Denmark; The Research Foundation, Capital Region of Denmark; The Ivan Nielsen Foundation; The A.P. Moeller and wife Chastine Mc-Kinney Moellers Family Foundation; The Augustinus Foundation; The Woerzner Foundation; Grosserer L.F Foghts Foundation; The Hartmann Foundation; The Aase and Ejnar Danielsen Foundation; The P.A. Messerschmidt and wife foundation and The Lundbeck Foundation. The funding sources and the manufacturer of exenatide once weekly (Bydureon®, AstraZeneca), had no influence on the trial design or data analysis.
Authors
Mette K. Klausen, Mathias E. Jensen, Marco Møller, Nina le Dous, Anne-Marie Ø Jensen, Victoria A. Zeeman, Claas-Frederik Johannsen, Alycia M. Lee, Gerda K. Thomsen, Julian Macoveanu, Patrick M Fisher, Matthew P. Gillum, Niklas R. Jørgensen, Marianne L. Bergmann, Henrik Enghusen Poulsen, Ulrik Becker, Jens Juul Holst, Helene Benveniste, Nora D. Volkow, Sabine Vollstädt-Klein, Kamilla W. Miskowiak, Claus T. Ekstrøm, Gitte M. Knudsen, Tina Visboll, Anders Fink-Jensen
Abstract
BACKGROUND. Systemic sclerosis (SSc) is an autoimmune, connective tissue disease characterized by vasculopathy and fibrosis of the skin and internal organs. METHODS. We randomized 15 participants with early diffuse cutaneous SSc to tofacitinib 5 mg twice a day or matching placebo in a Phase I/II double-blind, placebo-controlled trial. The primary outcome measure was safety and tolerability at or before Week 24. In order to understand the changes in gene expression associated with tofacitinib treatment in each skin cell populations, we compared single cell gene expression in punch skin biopsies obtained at baseline and 6 weeks following the initiation of treatment. RESULTS. Tofacitinib was well tolerated; there were no participants, who experienced Grade 3 or higher adverse effects (AEs) before or at Week 24. Trends in efficacy outcome measures favored tofacitnib. Baseline gene expression in fibroblast and keratinocyte subpopulations indicates interferon (IFN) activated gene expression. Tofacitinib inhibited IFN-regulated gene expression in the SFRP2/DPP4 fibroblasts (progenitors of myofibroblasts) and MYOC and CCL19, representing adventitial fibroblasts (p< 0.05), as well as in the basal and keratinized layers of the epidermis. Gene expression in macrophages and dendritic cells indicated inhibition of STAT3 by tofacitinib (p<0.05). No clinically meaningful inhibition of T cells and endothelial cells in the skin tissue was observed. CONCLUSION. These results indicate that mesenchymal and epithelial cells of a target organ in SSc, not the infiltrating lymphocytes, may be the primary focus for therapeutic effects of a janus kinase inhibitor. TRIAL REGISTRATION. clinicaltrials.gov NCT03274076. FUNDING SOURCE. This was an investigator-initiated trial designed by the Sponsor and the steering committee. The industry funder, Pfizer, had no role in collecting, analyzing, and interpreting the data. The manuscript was drafted by the authors and was reviewed by Pfizer Inc. before final submission. No medical writer was involved in creating the manuscript. DK was supported by NIH/NIAMS R01 AR070470 and NIH/NIAMS K24 AR063120. JMK, JEG, LCT are supported by the Taubman Medical Research Institute and NIH-P30 AR075043. LCT was also supported by NIH/NIAMS K01AR072129. The corresponding author had full access to all data congregates in the study and made the final decision to submit the manuscript for publication.
Authors
Dinesh Khanna, Cristina M. Padilla, Lam C. Tsoi, Vivek Nagaraja, Puja Khanna, Tracy Tabib, J. Michelle Kahlenberg, Amber Young, Suiyuan Huang, Johann e. Gudjonsson, David A. Fox, Robert Lafyatis
Immunogenic epitope panel for accurate detection of non-cross-reactive T cell response to SARS-CoV-2
Abstract
The ongoing COVID-19 pandemic calls for more effective diagnostic tools. T cell response assessment serves as an independent indicator of prior COVID-19 exposure while also contributing to a more comprehensive characterization of SARS-CoV-2 immunity. In this study, we systematically assessed the immunogenicity of 118 epitopes with immune cells collected from multiple cohorts of vaccinated, convalescent, healthy unexposed, and SARS-CoV-2 exposed donors. We identified 75 immunogenic epitopes, 24 of which were immunodominant. We further confirmed HLA restriction for 49 epitopes, and described association with more than one HLA allele for 14 of these. Exclusion of two cross-reactive epitopes that generated a response in pre-pandemic samples, left us with a 73-epitope set that offered excellent diagnostic specificity without losing sensitivity compared to full-length antigens, which evoked a robust cross-reactive response. We subsequently incorporated this set of epitopes into an in vitro diagnostic ‘Corona-T-test’ which achieved a diagnostic accuracy of 95% in a clinical trial. In a cohort of asymptomatic seronegative individuals with a history of prolonged SARS-CoV-2 exposure, we observed a complete absence of T cell response to our epitope panel. In combination with strong reactivity to full-length antigens, this suggests that a cross-reactive response might protect these individuals.
Authors
Aleksei Titov, Regina Shaykhutdinova, Olga V. Shcherbakova, Yana V. Serdyuk, Savely A. Sheetikov, Ksenia V. Zornikova, Alexandra V. Maleeva, Alexandra Khmelevskaya, Dmitry V. Dianov, Naina T. Shakirova, Dmitry B. Malko, Maxim Shkurnikov, Stepan Nersisyan, Alexander Tonevitsky, Ekaterina Khamaganova, Anton V. Ershov, Elena Y. Osipova, Ruslan V. Nikolaev, Dmitry E. Pershin, Viktoria A. Vedmedskia, Mikhail Maschan, Victoria R. Ginanova, Grigory A. Efimov
Abstract
BACKGROUND. Potent synthetic opioids, such as fentanyl, are increasingly abused, resulting in unprecedented numbers of fatalities from respiratory depression. Treatment with the high-affinity mu-opioid receptor partial agonist buprenorphine may prevent fatalities by reducing binding of potent opioids to the opioid receptor, limiting respiratory depression. METHODS. To characterize buprenorphine-fentanyl interaction at the level of the mu-opioid receptor in two populations (opioid-naïve individuals and chronic users of high-dose opioids), the effects of escalating intravenous fentanyl doses with range 0.075-0.35 mg/70kg (opioid-naïve) and 0.25-0.70 mg/70 kg (chronic opioid users) on iso-hypercapnic ventilation at 2-3 background doses of buprenorphine (target plasma concentrations range: 0.2-5 ng/mL) were quantified using receptor association/dissociation models combined with biophase distribution models. RESULTS. Buprenorphine produced mild respiratory depression, while high doses of fentanyl caused pronounced respiratory depression and apnea in both populations. When combined with fentanyl, buprenorphine produced a receptor binding-dependent reduction of fentanyl-induced respiratory depression in both populations. In chronic opioid users, at buprenorphine plasma concentrations ≥2 ng/mL, a protective effect against high-dose fentanyl was observed. CONCLUSION. Overall, the results indicate that when buprenorphine mu-opioid receptor occupancy is sufficiently high, fentanyl is unable to activate the mu-opioid receptor and consequently will not cause further respiratory depression in addition to the mild respiratory effects of buprenorphine. TRIAL REGISTRATION. Trialregister.nl, number NL7028 (https://www.trialregister.nl/trial/7028) FUNDING. Indivior Inc., North Chesterfield, VA.
Authors
Erik Olofsen, Marijke Hyke Algera, Laurence Moss, Robert L. Dobbins, Geert J. Groeneveld, Monique van Velzen, Marieke Niesters, Albert Dahan, Celine M. Laffont
A 4-week high-AGE diet does not impair glucose metabolism and vascular function in obese individuals
Abstract
BACKGROUND. Accumulation of advanced glycation endproducts (AGEs) may contribute to the pathophysiology of type 2 diabetes and its vascular complications. AGEs are widely present in food, but whether restricting AGE intake improves risk factors for type 2 diabetes and vascular dysfunction is controversial. RESEARCH DESIGN AND METHODS. Abdominally obese but otherwise healthy individuals were randomly assigned to a specifically designed 4-week diet low or high in AGEs in a double blind parallel-design. Insulin sensitivity, secretion, and clearance were assessed by a combined hyperinsulinemic-euglycemic and hyperglycemic clamp. Micro- and macrovascular function, inflammation, and lipid profile were assessed by state-of-art in vivo measurements and biomarkers. Specific urinary and plasma AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were assessed by mass spectrometry. RESULTS. In 73 individuals (22 males, mean ± SD age and BMI 52 y ± 14, 30.6 kg/m2 ± 4.0), intake of CML, CEL, and MG-H1 differed 2.7, 5.3, and 3.7-fold between the low and high AGE diets, which led to corresponding changes of these AGEs in urine and plasma. Despite this, there was no difference in insulin sensitivity, secretion, or clearance, micro- and macrovascular function, overall inflammation, or lipid profile between the low and high dietary AGE groups (all p for treatment effects > 0.05). CONCLUSIONS. This comprehensive RCT demonstrates very limited biological consequences of a 4-week diet low or high in AGEs in abdominally obese individuals. TRIAL REGISTRATION. clinicaltrials.gov: NCT03866343, trialregister.nl: NTR7594. FUNDING. Diabetesfonds and ZonMw.
Authors
Armand M A Linkens, Alfons J. Houben, Petra M Niessen, Nicole Wijckmans, Erica de Goei, Mathias D.G. Van den Eynde, Jean L. J. M. Scheijen, Marjo Waarenburg, Andrea Mari, Tos T.J.M. Berendschot, Lukas Streese, Henner Hanssen, Martien C.J.M. van Dongen, Christel van Gool, Coen D.A. Stehouwer, Simone JPM Eussen, Casper Schalkwijk.
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