Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of ...tofacitinib as induction and maintenance therapy.
We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks.
In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels.
In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.).
Summary
Background
Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC).
Aim
To report incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) ...in the tofacitinib UC programme.
Methods
DVT and PE were evaluated from one phase 2 and two phase 3 induction studies, one phase 3 maintenance study and an ongoing, open‐label, long‐term extension (OLE) study (September 2018 datacut). Data were analysed in induction, maintenance and overall (patients receiving ≥ 1 dose of tofacitinib 5 or 10 mg b.d. in any phase 2, 3 or OLE study) cohorts.
Results
1157 patients (2404 patient‐years’ exposure; ≤ 6.1 years’ tofacitinib treatment) were evaluated in the overall cohort. In induction, one placebo‐treated patient had DVT and one had PE; no tofacitinib‐treated patients had DVT/PE. In maintenance, one placebo‐treated patient had DVT and one had PE; no tofacitinib‐treated patients had DVT/PE. In the overall cohort, one patient had DVT (incidence rate patients with events/100 patient‐years; 95% CI: 0.04 0.00‐0.23); four had PE (0.16 0.04‐0.41); all received predominant dose tofacitinib 10 mg b.d.; all had venous thromboembolism risk factors alongside UC.
Conclusions
In this post hoc analysis of patients with UC, during tofacitinib exposure, one patient had DVT and four had PE, all during the OLE study, on predominant dose 10 mg b.d. (83% of overall cohort patients received predominant dose 10 mg b.d.) with venous thromboembolism risk factors. This analysis is limited by small sample size and limited drug exposure; further studies are needed. ClinicalTrials.gov: NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.
Therapeutic strategies in ulcerative colitis are evolving. A personalized and optimal use of available drugs and the integration of new drug classes are the cornerstones underpinning the new ...treatment paradigms. Areas covered: A structured literature search in Medline and PubMed, Cochrane meta-analyses, and abstracts of international congresses has been performed to review therapeutic approaches to ulcerative colitis. The primary therapeutic objective of therapy is to achieve clinical remission since persistence of active disease, even if mild, leads to a significant reduction in quality of life. Current treatment paradigms of ulcerative colitis are based on the use of 5-aminosalycilates, corticosteroids, thiopurines, TNF-α inhibitors and α4ß7 integrin blockers. The main determinants for drug class selection are disease extension, disease severity, and previous drug history. New drug classes that will likely become available in the foreseeable future include inhibitors of Janus kinases, modulators of sphingosine-1-phosphate receptors, SMAD-7 antisense oligonucleotides, interleukin-12/23 blockers, and fecal microbiota transplantation. Expert commentary: Increasing therapeutic options for ulcerative colitis make predictors of response highly relevant. While these are not available, judicious use of therapies, avoidance of underdosing, or persistent therapy when criteria for drug failure are met are essential.
Ulcerative colitis and Crohn's disease are chronic inflammatory intestinal diseases with perplexing heterogeneity in disease manifestation and response to treatment. While the molecular basis for ...this heterogeneity remains uncharacterized, single-cell technologies allow us to explore the transcriptional states within tissues at an unprecedented resolution which could further understanding of these complex diseases. Here, we apply single-cell RNA-sequencing to human inflamed intestine and show that the largest differences among patients are present within the myeloid compartment including macrophages and neutrophils. Using spatial transcriptomics in human tissue at single-cell resolution (CosMx Spatial Molecular Imaging) we spatially localize each of the macrophage and neutrophil subsets identified by single-cell RNA-sequencing and unravel further macrophage diversity based on their tissue localization. Finally, single-cell RNA-sequencing combined with single-cell spatial analysis reveals a strong communication network involving macrophages and inflammatory fibroblasts. Our data sheds light on the cellular complexity of these diseases and points towards the myeloid and stromal compartments as important cellular subsets for understanding patient-to-patient heterogeneity.
Darvadstrocel is an expanded allogeneic adipose-derived mesenchymal stem cell therapy for the treatment of complex perianal fistulas in patients with Crohn's disease. Safety and efficacy outcomes ...from the clinical trial known as "Adipose derived mesenchymal stem cells for induction of remission in perianal fistulizing Crohn's disease," or ADMIRE-CD (NCT01541579), from up to 52 weeks posttreatment were previously reported. Here, the outcomes from an extended 104-week follow-up are reported.
The goal of this study was to assess the long-term safety and efficacy of darvadstrocel at 2 years post-treatment in patients with Crohn's disease and complex perianal fistulas.
This was a phase 3 double-blind randomized controlled study (ADMIRE-CD) in patients with perianal fistulizing Crohn's disease.
This study extension was conducted in multiple hospitals across 7 European countries and Israel.
Forty patients entered the extended follow-up period: 25 patients in the darvadstrocel treatment group and 15 in the control group.
Darvadstrocel or saline solution (control group) was administered once, locally, after fistula tract curettage and internal opening closure (with previous seton placement). All patients were permitted to continue ongoing medical treatments for fistulas.
Treatment-emergent serious adverse events were recorded through week 104. Clinical remission, defined as closure of all treated external openings that were draining at baseline despite gentle finger compression, was assessed at week 104.
Of 40 patients, 37 completed the extended follow-up. Through week 104, 7 treatment-emergent serious adverse events were reported, of which 4 occurred between weeks 52 and 104. At week 104, clinical remission was reported in 14/25 (56%) patients in the darvadstrocel group and 6/15 (40%) patients in the control group.
Limitations include the small number of patients who entered the extended follow-up period, and no imaging examinations were performed at the 104-week time point.
Darvadstrocel was well tolerated and clinical remission after treatment with darvadstrocel may be sustained for up to 104 weeks in patients with perianal fistulizing Crohn's disease. See Video Abstract at http://links.lww.com/DCR/B812.ClinicalTrials.gov No: NCT01541579.
ANTECEDENTES:Darvadstrocel es una terapia con células madre mesenquimales alogénicas expandidas derivadas de tejido adiposo para el tratamiento de fístulas perianales complejas en pacientes con enfermedad de Crohn. Los resultados del ensayo clínico conocido como "Células madre mesenquimales derivadas de tejido adiposo para la inducción de la remisión en la enfermedad de Crohn fistulizante perianal" o ADMIRE-CD (NCT01541579), en cuanto a la seguridad y eficacia hasta 52 semanas después del tratamiento, fueron previamente informados. Seguidamente, se presentan los resultados de un seguimiento extendido de 104 semanas.OBJETIVO:Evaluar la seguridad y eficacia a largo plazo de darvadstrocel a dos años del tratamiento en pacientes con enfermedad de Crohn y fístulas perianales complejas.DISEÑO:Este fue un estudio de fase 3, aleatorizado, a doble ciego, controlado (ADMIRE-CD) en pacientes con enfermedad de Crohn perianal fistulizante.DESARROLLO:Esta extensión del estudio se realizó en varios hospitales de siete países europeos e Israel.PACIENTES:Cuarenta pacientes participaron en la extensión de seguimiento: tratamiento con darvadstrocel (n = 25); grupo control (n = 15).INTERVENCIONES:Se administró Darvadstrocel o solución salina (grupo control) una vez, localmente, tras el legrado del trayecto fístuloso y cierre del orificio interno (con la colocación previa de setón). A todos los pacientes se les permitió continuar con los tratamientos médicos en curso para las fístulas.PRINCIPALES MEDIDAS DE RESULTADO:Los eventos de efectos adversos graves derivados del tratamiento se registraron hasta la semana 104. La remisión clínica, definida como el cierre de todas las aberturas externas tratadas que drenaban al inicio espontáneamente o por compresión suave de los dedos, fue evaluado en la semana 104.RESULTADOS:Del total de 40 pacientes, 37 completaron la extensión de seguimiento. Hasta la semana 104, se reportaron 7 eventos de efectos adversos graves resultantes del tratamiento, de los cuales 4 ocurrieron entre las semanas 52 y 104. En la semana 104, se reportó remisión clínica en 14/25 (56%) pacientes en el grupo de darvadstrocel y 6/15 (40%) pacientes en el grupo de control.LIMITACIONES:Solo una pequeña cantidad de pacientes participaron en el período de seguimiento extendido y no se realizaron exámenes por técnicas de imagen en la visita a 104 semanas.CONCLUSIONES:Darvadstrocel fue bien tolerado y la remisión clínica después del tratamiento con darvadstrocel puede mantenerse hasta 104 semanas en pacientes con enfermedad de Crohn perianal fistulizante. Consulte Video Resumen en http://links.lww.com/DCR/B812. (Traducción-Dr Osvaldo Gauto and Dr Julian Panés.)ClinicalTrials.gov No. NCT01541579.
Through genome-wide association scans and meta-analyses thereof, over 70 genetic loci (Crohn's disease (CD) single nucleotide polymorphisms (SNPs)) are significantly associated with CD. We aimed to ...investigate the influence of CD-SNPs and basic patient characteristics on CD clinical course, and develop statistical models to predict CD clinical course.
This retrospective study included 1528 patients with CD with more than 10 years of follow-up from eight European referral hospitals. CD outcomes of interest were ileal (L1), colonic (L2) and ileocolonic disease location (L3); stenosing (B2) or penetrating behaviour (B3); perianal disease; extraintestinal manifestations; and bowel resection. A complicated disease course was defined as stenosing or penetrating behaviour, perianal disease and/or bowel resection. Association between CD-SNPs or patient characteristics and specified outcomes was studied.
Several CD-SNPs and clinical characteristics were statistically associated with outcomes of interest. The NOD2 gene was the most important genetic factor, being an independent predictive factor for ileal location (p=2.02 × 10(-06), OR=1.90), stenosing (p=3.16 × 10(-06), OR=1.82) and penetrating (p=1.26 × 10(-02), OR=1.25) CD behaviours, and need for surgery (p=2.28 × e-05, OR=1.73), and as such was also the strongest factor associated with a complicated disease course (p=6.86 × 10(-06), OR=2.96). Immunomodulator (azathioprine/6-mercaptopurine and methotrexate) use within 3 years after diagnosis led to a reduction in bowel stenoses (p=1.48 × 10(-06), OR=0.35) and surgical rate (p=1.71 × 10(-07), OR=0.34). Association between each outcome and genetic scores, created using significant SNPs in the univariate analysis, revealed large differences in the probability of developing fistulising disease (IL23R, LOC441108, PRDM1, NOD2; p=9.64e-4, HR=1.43), need for surgery (IRGM, TNFSF15, C13ORF31, NOD2; p=7.12 × 10(-03), HR=1.35), and stenosing disease (NOD2, JAK2, ATG16L1; p=3.01 × 10(-02), HR=1.29) among patients with low and high score.
This large multicentre cohort study has found several genetic and clinical factors influencing the clinical course of CD. NOD2 and early immunomodulator use are the clinically most meaningful predictors for its clinical course.
Background & Aims Accurate biomarkers of disease activity and therapeutic response can be valuable for clinical trials. We performed a post hoc analysis of data from a phase 2 trial to assess the ...relationship between the concentration of fecal calprotectin (FCP) and clinical and endoscopic outcomes of patients with moderate to severe ulcerative colitis receiving tofacitinib. Methods In a double-blind, placebo-controlled, phase 2 trial, 194 patients were assigned randomly to groups given tofacitinib (0.5, 3, 10, or 15 mg twice daily) or placebo. Clinical and endoscopic outcomes were assessed at week 8 using the Mayo scoring system. Receiver operating characteristics were used to evaluate the relationships between FCP concentration and clinical and endoscopic outcomes, and to determine the FCP cut-off concentration that correlated with patient outcome. Results Week 8 median concentrations of FCP were significantly lower in responders than in nonresponders ( P < .001): clinical response, 156 vs 725 mg/kg; clinical remission, 64 vs 617 mg/kg; endoscopic remission, 44 vs 489 mg/kg; and mucosal healing, 127 vs 753 mg/kg. Area-under-the-curve values for FCP receiver operating characteristic models were 0.80 for clinical remission, 0.81 for endoscopic remission, and 0.78 for mucosal healing. An FCP cut-off value of 150 mg/kg achieved the highest summation of sensitivity and specificity for clinical remission (0.68 and 0.79, respectively; κ coefficient, 0.44) and endoscopic remission (0.79 and 0.75, respectively; κ coefficient, 0.38). Conclusions Concentrations of FCP correlate with clinical and endoscopic outcomes of patients with moderate to severe ulcerative colitis receiving tofacitinib, although at an individual level the agreement was moderate. FCP concentration with a cut-off value of 150 mg/kg had only fair to good accuracy in classifying clinical and endoscopic outcomes in a clinical trial. ClinicalTrials.gov no: NCT00787202.
Crohn's disease (CD) is a chronic progressive destructive disease. Currently available instruments measure disease activity at a specific point in time. An instrument to measure cumulative structural ...damage to the bowel, which may predict long‐term disability, is needed. The aim of this article is to outline the methods to develop an instrument that can measure cumulative bowel damage. The project is being conducted by the International Program to develop New Indexes in Crohn's disease (IPNIC) group. This instrument, called the Crohn's Disease Digestive Damage Score (the Lémann score), should take into account damage location, severity, extent, progression, and reversibility, as measured by diagnostic imaging modalities and the history of surgical resection. It should not be “diagnostic modality driven”: for each lesion and location, a modality appropriate for the anatomic site (for example: computed tomography or magnetic resonance imaging enterography, and colonoscopy) will be used. A total of 24 centers from 15 countries will be involved in a cross‐sectional study, which will include up to 240 patients with stratification according to disease location and duration. At least 120 additional patients will be included in the study to validate the score. The Lémann score is expected to be able to portray a patient's disease course on a double‐axis graph, with time as the x‐axis, bowel damage severity as the y‐axis, and the slope of the line connecting data points as a measure of disease progression. This instrument could be used to assess the effect of various medical therapies on the progression of bowel damage. (Inflamm Bowel Dis 2011)
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