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Nilotinib (Tasigna) in the Treatment of Early Diffuse Systemic Sclerosis: An Open-Label, Pilot Clinical Trial

ABSTRACT: To assess the safety, efficacy, and molecular change associated with treatment of patients with early, diffuse cutaneous systemic sclerosis (dcSSc) with nilotinib (Tasigna™). In this open-label pilot trial 6 adult patients with early dcSSc received nilotinib. Primary endpoints were safety and change in modified Rodnan Skin Score (MRSS) after 6 months. Lesional skin biopsies at baseline, 6 and 12 months of treatment were assessed by histopathology, immunohistochemistry, and DNA microarray.

ORGANISM(S): Homo sapiens

SUBMITTER: Tammara Wood

PROVIDER: E-GEOD-65405 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Nilotinib (Tasigna™) in the treatment of early diffuse systemic sclerosis: an open-label, pilot clinical trial.

Gordon Jessica K JK Martyanov Viktor V Magro Cynthia C Wildman Horatio F HF Wood Tammara A TA Huang Wei-Ti WT Crow Mary K MK Whitfield Michael L ML Spiera Robert F RF

Arthritis research & therapy 20150818

<h4>Introduction</h4>Tyrosine kinase inhibitors (TKI) are medications of interest in the treatment of Systemic Sclerosis (SSc) because of their ability to inhibit pathways involved in fibrosis. In this open-label pilot trial, our objectives were to assess the safety, efficacy, and molecular change associated with treatment of patients with diffuse cutaneous (dc)SSc with the TKI nilotinib (Tasigna™).<h4>Methods</h4>Ten adult patients with early dcSSc were treated with nilotinib. Primary endpoints ...[more]

PMID: 26283632

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Nilotinib (Tasigna) in the Treatment of Early Diffuse Systemic Sclerosis: An Open-Label, Pilot Clinical Trial

Project description:To assess the safety, efficacy, and molecular change associated with treatment of patients with early, diffuse cutaneous systemic sclerosis (dcSSc) with nilotinib (Tasigna™).

2015-08-27 | GSE65405 | GEO

Pilot open label clinical trial of oral ruxolitinib in patients with alopecia areata

Project description:This goal of these studies were to examine gene expression profiles of skin from patients with alopecia areata undergoing treatment with oral ruxoltinib. Microarray analysis was performed to assess changes in gene expression in affected scalp skin.

2017-08-23 | GSE80342 | GEO

Systemic sclerosis skin disease trajectory during mycophenolate mofetil treatment

Project description:Background: Only a subset of patients with systemic sclerosis (SSc) demonstrate improvement in modified Rodnan skin score (mRSS) during mycophenolate mofetil (MMF) treatment. Here we investigated the molecular and cellular effects in skin associated with MMF therapy in subjects who demonstrated or lacked clinical improvement. Methods: Clinical and skin gene expression data were obtained genome-wide from baseline and longitudinal (6-, 12-, 24-, and 36-mo) biopsies in 33 MMF-treated subjects with SSc. Clinical improvement was defined as mRSS reduction ≥ 25%. An inflammatory signature score was calculated for each patient sample using single-sample gene set enrichment analysis (ssGSEA). Cell type specific changes during treatment were characterized. Results: Eleven subjects with SSc completed at least 24 months of MMF therapy and were termed ‘completers’. Two distinct gene expression patterns were observed that corresponded to MMF treatment status. Three subjects showed attenuation of the inflammatory signature by 24 months, paralleling reductions in activated dendritic cells. MMF cessation at 24 months resulted in an inflammatory signature rebound paralleling mRSS increase. Three subjects that remained on MMF showed persistent inflammatory signature reductions with decreasing or stable mRSS. The remaining six completers either did not fulfill minimum mRSS (n=5), and/or lacked a baseline inflammatory signature (n=4). Conclusions: An elevated inflammatory skin gene expression signature is associated with clinical improvement during MMF therapy. Inflammation returned upon MMF discontinuation with concomitant mRSS increase. These data summarize MMF’s molecular effects in skin and support MMF therapy for longer than 24 months in patients who demonstrate clinical response.

2017-01-01 | GSE76885 | GEO

A phase 2, open label single arm study for evaluating safety & efficacy of apremilast in the treatment of cutaneous disease in patients with recalcitrant dermatomyositis.

Project description:Purpose: Studying the efficacy and safety of apremilast as an add-on therapy in patients with recalcitrant cutaneous dermatomyositis. Studying the mechanism of action of apremilast in dermatomyositis by performing RNA sequencing and immunohistochemistry on skin biopsies before and after treatment. Methods: We enrolled 8 patients with recalcitrant dermatomyositis. Apremilast 30 mg orally twice daily was added to a stable treatment regimen of steroids and/or steroids sparing agents and patients were followed for 7 months. A CDASI, muscle score, dermatology life quality index (DLQI), and depression assessments were performed at baseline and regularly till month 7. Skin biopsies were performed at baseline and 3-months post-apremilast to study gene expression alterations. Results: Our ORR assessed at 3 months post apremilast was 87.5%. The response was maintained at 6 months with continued decrease in CDASI and improvement in DLQI. The mean decrease in CDASI was 12.9 points (p<0.05). Apremilast was well tolerated and without any grade 3 or higher adverse events using CTCAE version 5. RNA sequencing was performed on skin biopsies from 7 patients before and 3 months after apremilast. Out of 39,076 expressed genes, there were 195 whose expression changed ≥2-fold at P<0.01 (123 down- and 72 up-regulated), several genes are known JAK-STAT targets. Using GSEA analysis, we identified 13 pathways significantly downregulated by apremilast, notably STAT1, STAT3, IL-2, IL-6, IL-12, IL-23, INFγ, and TNFα pathways. Immunohistochemical staining confirmed JAK/STAT signaling inhibition at the protein level. Conclusions: Apremilast is a safe and efficacious add-on treatment in recalcitrant dermatomyositis with an overall response rate of 87.5%, and functions through downregulation of JAK/STAT signaling in dermatomyositis.

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Machine-learning Classification Identifies Early Systemic Sclerosis Patients that Improve with Abatacept treatment by Modulating CD28-Pathways

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A pilot open label, single dose trial of fenobam in adults with fragile X syndrome.

Project description:A pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS).Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition.There were no significant adverse reactions to fenobam administration. Pharmacokinetic analysis showed that fenobam concentrations were dose dependent but variable, with mean (SEM) peak values of 39.7 (18.4) ng/ml at 180 min after the 150 mg dose. PPI met a response criterion of an improvement of at least 20% over baseline in 6 of 12 individuals (4/6 males and 2/6 females). The CPT did not display improvement with treatment due to ceiling effects.Clinically significant adverse effects were not identified in this study of single dose fenobam across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS.

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Injectable hyaluronan for the treatment of carpometacarpal osteoarthritis: open label pilot trial.

Project description:ObjectiveCarpometacarpal osteoarthritis (CMC OA) is highly prevalent in older adults, and is often unresponsive to medical treatment. Intra-articular Hylan G-F 20 has been shown to improve pain and function in patients with knee OA; however, its effectiveness in CMC OA is less clear.Methods32 patients with CMC OA were injected with Hylan G-F 20, once weekly for three consecutive weeks. Patients were assessed 4, 12, 20 and 26 weeks after the first injection. A last-value carried forward analysis was performed.ResultsAverage age was 64 years, (range 46-79), 69% were female and 97% Caucasian. Fifty-three percent had at least one previous corticosteroid injection in the affected CMC joint. At 26 weeks, mean visual analogue scale (VAS) for pain had improved significantly (15.2 mm; p-value = 0.006). Disabilities of the arm, shoulder and hand questionnaire (DASH) scores also improved significantly (12.6; p-value < 0.001). A DASH change of 10-14 is considered clinically meaningful. Neither key strength nor opposition grip strength improved. VAS scores for pain at 26 weeks showed good correlation with patient satisfaction (Spearman r = 0.52, p-value < 0.01). Adverse events potentially related to the injections included three episodes of post-injection pain and swelling, and one case of crystal proven pseudogout.ConclusionIntra-articular Hylan G-F 20 injections reduced pain and improved function in patients with CMC OA at 26 weeks in this small open label study. Limitations of this study include its small, open label design. Larger randomized controlled trials are needed to confirm these results, and to determine predictors of response to treatment.Clinical trial registrationThis study was approved by the Institutional Review Board at the Hospital for Special Surgery, New York, NY, USA and registered at (www.ClinicalTrials.Gov)# NCT00198029.

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Molecular Signatures in Skin Associated with Clinical Improvement During Mycophenolate Treatment in Systemic Sclerosis

Project description:Skin gene expression signatures, including intrinsic subset, are associated with skin score/MRSS improvement during mycophenolate mofetil (MMF) treatment.

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2017-09-08 | GSE73634 | GEO

Ethosuximide for Essential Tremor: An Open-Label Trial.

Project description:T-type calcium channel activation has been postulated to underlie rhythmicity in the olivo-cerebellar system that is implicated in ET. Ethosuximide reduces T-type calcium currents and can suppress tremor in two animal models of ET. We explored the effects of ethosuximide in subjects with ET in an open-label trial using both clinical scales and accelerometric recordings measures. We initially planned to conduct the trial with 15 patients, but due to lack of efficacy and a high incidence of adverse effects, the trial was stopped after seven patients had participated.Seven patients diagnosed with ET were included in the study. The ethosuximide dose was 500 mg daily (BID). The main outcome measures were: 1) tremor clinical rating scale (TCRS) score, 2) accelerometric recordings, and 3) self-reported disability scale score.Five patients completed the study, and two dropped out due to adverse effects. There were no significant changes in clinical scores in motor task performance (TCRS 1+2), daily living activities (TCRS 3), or in the patients' subjective assessment (TCRS 4) and global appraisal. There were no differences observed for accelerometry data or disability scale scores. Anxiety, nervousness, headache, and dizziness were reported by two patients while on ethosuximide, causing them to stop the trial. No patient preferred to continue ethosuximide treatment.The results of our exploratory study suggest that ethosuximide is not an effective treatment for ET.

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