BACKGROUND Slow-flow vascular malformations frequently harbor activating mutations in the PI3K/AKT/mTOR cascade. Phase II trials pinpointed sirolimus effectiveness as a drug therapy. Efficacy and safety of sirolimus thus need to be evaluated in large prospective phase III trials.METHODS The Vascular Anomaly-Sirolimus-Europe (VASE) trial, initiated in 2016, is a large multicentric prospective phase III trial (EudraCT 2015-001703-32), which evaluates efficacy and safety of sirolimus for 2 years in pediatric and adult patients with symptomatic slow-flow vascular malformations. In this interim analysis, we studied all patients enrolled up to October 2021 who received sirolimus for 12 or more months or who prematurely stopped the treatment.RESULTS Thirty-one pediatric and 101 adult patients were included in this analysis; 107 completed 12 or more months of sirolimus, including 61 who were treated for the whole 2-year period. Sirolimus resulted in a clinical improvement in 85% of patients. The efficacy appeared within the first month for the majority of them. Grade 3–4 adverse events were observed in 24 (18%) patients; all resolved after treatment interruption/arrest. Sirolimus increased feasibility of surgery or sclerotherapy in 20 (15%) patients initially deemed unsuitable for intervention. Among the 61 patients who completed the 2-year treatment, 33 (54%) reported a recurrence of symptoms after a median follow-up of 13 months after sirolimus arrest. While there was no difference in efficacy, clinical improvement was faster but subsided more rapidly in PIK3CA-mutated (n = 24) compared with TIE2-mutated (n = 19) patients.CONCLUSION Sirolimus has a high efficacy and good tolerance in treatment of slow-flow vascular malformations in children and adults.TRIAL REGISTRATION ClinicalTrials.gov NCT02638389 and EudraCT 2015-001703-32.FUNDING The Fonds de la Recherche Scientifique (FNRS grants T.0247.19, P.C005.22, T.0146.16, and P.C013.20), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO-CR-2019C-06), the MSCA-ITN network V.A. Cure no. 814316, the Leducq Foundation Networks of Excellence Program grant “ReVAMP” (LFCR grant 21CVD03), the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 874708 (Theralymph), the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694, and a Pierre M. fellowship.
Emmanuel Seront, An Van Damme, Catherine Legrand, Annouk Bisdorff-Bresson, Philippe Orcel, Thomas Funck-Brentano, Marie-Antoinette Sevestre, Anne Dompmartin, Isabelle Quere, Pascal Brouillard, Nicole Revencu, Martina De Bortoli, Frank Hammer, Philippe Clapuyt, Dana Dumitriu, Miikka Vikkula, Laurence M. Boon
BACKGROUND. Severe forms of idiopathic nephrotic syndrome require prolonged immune-suppressive therapies and repeated courses of high-dose glucocorticoids. Mesenchymal stromal cells (MSCs) have promising immunomodulatory properties that may be employed therapeutically to reduce patient exposure to medications and their side effects. METHODS. We performed a phase 1 open-label trial assessing safety and feasibility of autologous bone marrow-derived (BM) MESenchymal stromal cells in children and young adults with severe forms of steroid-dependent NEPHrotic syndrome, (MESNEPH). Following autologous BM-MSC preparation and infusion, oral immunosuppression was tapered. Safety, efficacy and immunomodulatory effects in vivo were monitored for 12 months. RESULTS. Sixteen patients (10 children, 6 adults) were treated. Adverse events were limited and not related to BM-MSC infusions. All patients relapsed during follow-up, but in the 10 treated children, time to first relapse was delayed (p=0.02) and number of relapses was reduced (p=0.002) after BM-MSC infusion, compared to the previous 12 months. Cumulative prednisone dose was also reduced at 12 months compared to baseline (p<0.05). No treatment benefit was observed in adults. In children, despite tapering of immunosuppression, clinical benefit was mirrored by a significant reduction of total CD19+, mature and memory B cells and an increase of regulatory T cells in vivo up to 3-6 months following BM-MSC infusion. CONCLUSION. Treatment with autologous BM-MSC is feasible and safely reduces relapses and immunosuppression at 12 months in children with severe steroid-dependent INS. Immunomodulatory studies suggest that repeating MSC infusions at 3-6 months may sustain benefit. TRIAL REGISTRATION. EudraCT 2016-004804-77 FUNDING. AIFA Ricerca Indipendente 2016-02364623
Marina Vivarelli, Manuela Colucci, Mattia Algeri, Federica Zotta, Francesco Emma, Ines L'Erario, Marco Busutti, Stefano Rota, Chiara Capelli, Martino Introna, Marta Todeschini, Federica Casiraghi, Annalisa Perna, Tobia Peracchi, Andrea De Salvo, Nadia Rubis, Franco Locatelli, Giuseppe Remuzzi, Piero Ruggenenti
BACKGROUND. Current studies suggest mitochondrial dysfunction is a major contributor to impaired physical performance and exercise intolerance in chronic kidney disease (CKD). We conducted a clinical trial of coenzyme Q10 (CoQ10) and nicotinamide riboside (NR) to determine their impact on exercise tolerance and metabolic profile in CKD patients. METHODS. We conducted a randomized placebo-controlled, double blind, cross-over trial comparing CoQ10, NR, and placebo in 25 patients with eGFR of <60ml/min/1.73m2. Subjects received NR (1000 mg/day), CoQ10 (1200 mg/day), or placebo for 6 weeks each. Primary outcomes were aerobic capacity (VO2 peak) and work efficiency measured using graded cycle ergometry testing. We performed semi-targeted plasma metabolomics and lipidomics. RESUTS. Participant mean age was 61.0 ± 11.6 years and mean eGFR was 36.9±9.2 ml/min/1.73m2. Compared to placebo, we found no differences in VO2 peak (P=0.30, 0.17), total work (P=0.47, 0.77), and total work efficiency (P=0.46, 0.55) post NR or CoQ10 supplementation. NR decreased submaximal VO2 at 30W (P=0.03) and VO2 at 60W (P=0.07) compared to placebo. No changes in eGFR were observed post-NR or CoQ10 (P=0.14, 0.88). CoQ10 increased free fatty acids and decreased complex medium/long chain triglycerides. NR supplementation significantly altered TCA cycle intermediates and glutamate that are involved in reactions that exclusively use NAD+ and NADP+ as cofactors. NR decreased a broad range of lipid groups including triglycerides and ceramides. CONCLUSIONS. Six-weeks of treatment with NR or CoQ10 improved markers of systemic mitochondrial metabolism and lipid profiles but did not improve VO2 peak or total work efficiency. TRIAL REGISTRATION. ClinicalTrials.gov (NCT03579693) FUNDING. This study was supported by National Institutes of Diabetes and Digestive Kidney Diseases R01 DK101509 (to BK), R03 DK114502 (to BR), R01 DK125794 (to BR), R01 DK101509 (to JG), Dialysis Clinics Incorporated C-4112 (to BR), Northern California VA Health Care System (BR).
Armin Ahmadi, Gwenaelle Begue, Ana P. Valencia, Jennifer E. Norman, Benjamin Lidgard, Brian J. Bennett, Matthew P. Van Doren, David J. Marcinek, Sili Fan, David K. Prince, Jorge L. Gamboa, Jonathan Himmelfarb, Ian H. de Boer, Bryan R. Kestenbaum, Baback Roshanravan
BACKGROUND. Due to their immunoregulatory and tissue regenerative features, mesenchymal stromal cells (MSCs) are a promising novel tool for the management of ulcerative proctitis (UP). Here we report on a phase IIa clinical study to evaluate the impact of local MSC therapy in UP. METHODS. Thirteen refractory UP patients, with endoscopic Mayo score (EMS) 2 or 3, were included. Seven patients received 20-40 x 106 allogeneic MSCs (cohort 1), while six patients received 40-80 x 106 MSCs (cohort 2). Adverse events (AEs) were assessed at baseline and week 2, 6, 12, and 24. Clinical, endoscopic, and biochemical parameters were assessed at baseline, week 2 and 6. Furthermore, we evaluated the engraftment of MSCs, presence of donor-specific human leukocyte antigen (HLA) antibodies (DSAs), and we determined the impact of MSC therapy on the local immune compartment. RESULTS. No serious AEs were observed. The clinical Mayo score was significantly improved at week 2 and 6, and the EMS was significantly improved at week 6, compared to baseline. At week 6, donor MSCs were still detectable in rectum biopsies of 4/9 patients and DSAs against both HLA-class I and -class II were found. Mass cytometry showed a reduction of activated CD8+ T cells and CD16+ monocytes and an enrichment in mononuclear phagocytes and natural killer cells in biopsies after local MSC therapy. CONCLUSION. Local administration of allogeneic MSCs is safe, tolerable, and feasible for treatment of refractory UP and shows encouraging signs of clinical efficacy and modulation of local immune responses. This sets the stage for larger clinical trials. TRIAL REGISTRATION. clinicaltrialsregister.eu, EudraCT: 2017-003524-75, Dutch Trial register: NTR7205. FUNDING. ECCO grant 2020.
Laura F. Ouboter, Marieke C. Barnhoorn, Hein W. Verspaget, Leonie Plug, Emma S. Pool, Karoly Szuhai, Lukas J.A.C. Hawinkels, Melissa van Pel, Jaap Jan Zwaginga, Dave Roelen, Frits Koning, M. Fernanda Pascutti, Andrea van der Meulen - de Jong
BACKGROUND Chronic kidney disease (CKD) is characterized by chronic overactivation of the sympathetic nervous system (SNS), which increases the risk of cardiovascular (CV) disease and mortality. SNS overactivity increases CV risk by multiple mechanisms, including vascular stiffness. We tested the hypothesis that aerobic exercise training would reduce resting SNS activity and vascular stiffness in patients with CKD.METHODS In this randomized controlled trial, sedentary older adults with CKD underwent 12 weeks of exercise (cycling, n = 32) or stretching (an active control group, n = 26). Exercise and stretching interventions were performed 20–45 minutes/session at 3 days/week and were matched for duration. Primary endpoints include resting muscle sympathetic nerve activity (MSNA) via microneurography, arterial stiffness by central pulse wave velocity (PWV), and aortic wave reflection by augmentation index (AIx).RESULTS There was a significant group × time interaction in MSNA and AIx with no change in the exercise group but with an increase in the stretching group after 12 weeks. The magnitude of change in MSNA was inversely associated with baseline MSNA in the exercise group. There was no change in PWV in either group over the study period.CONCLUSION Our data demonstrate that 12 weeks of cycling exercise has beneficial neurovascular effects in patients with CKD. Specifically, exercise training safely and effectively ameliorated the increase in MSNA and AIx observed over time in the control group. This sympathoinhibitory effect of exercise training showed greater magnitude in patients with CKD with higher resting MSNA.TRIAL REGISTRATION ClinicalTrials.gov, NCT02947750.FUNDING NIH R01HL135183; NIH R61AT10457; NIH NCATS KL2TR002381; and NIH T32 DK00756; NIH F32HL147547; and VA Merit I01CX001065.
Jinhee Jeong, Justin D. Sprick, Dana R. DaCosta, Kevin Mammino, Joe R. Nocera, Jeanie Park
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.
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
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)).
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
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.
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
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.
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
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.
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
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