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BackgroundInterleukin-12 (IL-12) and interleukin-23 (IL-23) are inflammatory cytokines linked to the Th-1 and Th-17 phenotypes associated with Crohn's disease (CD). We investigated the activity and safety of apilimod mesylate (formerly STA-5326), an oral IL-12 and IL-23 inhibitor, in patients with active CD.MethodsWe performed a multicenter, Phase 2, randomized, double-blinded, placebo-controlled study to evaluate the efficacy of apilimod mesylate in treating 220 adult patients with moderate-to-severe CD (Crohn's Disease Activity Index [CDAI] score 220–450). Patients were stratified according to C-reactive protein (CRP) levels and corticosteroid use and were randomly assigned to receive placebo or apilimod mesylate 50 mg daily or 100 mg daily. The study was divided into an induction phase (43 days) and a maintenance phase (125 days). The primary analysis involved a comparison of the proportion of patients experiencing clinical response, defined as at least a 100-point decrease in CDAI score from baseline at day 29. Data on adverse events were also collected.ResultsIn all, 220 of the planned 282 patients were enrolled when the Data Monitoring Committee determined that the drug was not efficacious as a treatment and closed enrollment. A clinical response was experienced by 18 patients (24.7%) in the 50-mg daily (QD) group (n = 73) and 19 patients (25.7%) in the 100 mg QD group (n = 74), as compared with 21 patients (28.8%) in the placebo group (n = 73) on day 29 (P = 0.71 for each comparison). No significant adverse safety signal was observed.ConclusionsApilimod was well-tolerated but did not demonstrate efficacy over placebo in patients with active CD. (Inflamm Bowel Dis 2009)

There is a great unmet need for advanced therapies that provide rapid, robust, and sustained disease control for patients with ulcerative colitis. We assessed the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. This phase 3, multicentre, randomised, double-blind, placebo-controlled clinical programme consisted of two replicate induction studies (U-ACHIEVE induction [UC1] and U-ACCOMPLISH [UC2]) and a single maintenance study (U-ACHIEVE maintenance [UC3]). The studies were conducted across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 199 clinical centres in 39 countries (UC1), 204 clinical centres in 40 countries (UC2), and 195 clinical centres in 35 countries (UC3). Patients aged 16–75 years with moderately to severely active ulcerative colitis (Adapted Mayo score 5–9; endoscopic subscore 2 or 3) for at least 90 days were randomly assigned (2:1) to oral upadacitinib 45 mg once daily or placebo for 8 weeks (induction studies). Patients who achieved clinical response following 8-week upadacitinib induction were re-randomly assigned (1:1:1) to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks (maintenance study). All patients were randomly assigned using web-based interactive response technology. The primary endpoints were clinical remission per Adapted Mayo score at week 8 (induction) and week 52 (maintenance). The efficacy analyses in the two induction studies were based on the intent-to-treat population, which included all randomised patients who received at least one dose of treatment. In the maintenance study, the primary efficacy analyses reported in this manuscript were based on the first 450 (planned) clinical responders to 8-week induction therapy with upadacitinib 45 mg once daily. The safety analysis population in the induction studies consisted of all randomised patients who received at least one dose of treatment; in the maintenance study, this population included all patients who received at least one dose of treatment as part of the primary analysis population. These studies are registered at ClinicalTrials.gov, NCT02819635 (U-ACHIEVE) and NCT03653026 (U-ACCOMPLISH). Between Oct 23, 2018, and Sept 7, 2020, 474 patients were randomly assigned to upadacitinib 45 mg once daily (n=319) or placebo (n=155) in UC1. Between Dec 6, 2018, and Jan 14, 2021, 522 patients were randomly assigned to upadacitinib 45 mg once daily (n=345) or placebo (n=177) in UC2. In UC3, a total of 451 patients (21 from the phase 2b study, 278 from UC1, and 152 from UC2) who achieved a clinical response after 8 weeks of upadacitinib induction treatment were randomly assigned again to upadacitinib 15 mg (n=148), upadacitinib 30 mg (n=154), and placebo (n=149) in the primary analysis population. Statistically significantly more patients achieved clinical remission with upadacitinib 45 mg (83 [26%] of 319 patients in UC1 and 114 [34%] of 341 patients in UC2) than in the placebo group (seven [5%] of 154 patients in UC1 and seven [4%] of 174 patients; p<0·0001; adjusted treatment difference 21·6% [95% CI 15·8–27·4] for UC1 and 29·0% [23·2–34·7] for UC2). In the maintenance study, clinical remission was achieved by statistically significantly more patients receiving upadacitinib (15 mg 63 [42%] of 148; 30 mg 80 [52%] of 154) than those receiving placebo (18 [12%] of 149; p<0·0001; adjusted treatment difference 30·7% [21·7–39·8] for upadacitinib 15 mg vs placebo and 39·0% [29·7–48·2] for upadacitinib 30 mg vs placebo). The most commonly reported adverse events in UC1 were nasopharyngitis (15 [5%] of 319 in the upadacitinib 45 mg group vs six [4%] of 155 in the placebo group), creatine phosphokinase elevation (15 [4%] vs three [2%]), and acne (15 [5%] vs one [1%]). In UC2, the most frequently reported adverse event was acne (24 [7%] of 344 in the upadacitinib 45 mg group vs three [2%] of 177 in the placebo group). In both induction studies, serious adverse events and adverse events leading to discontinuation of treatment were less frequent in the upadacitinib 45 mg group than in the placebo group (serious adverse events eight [3%] vs nine (6%) in UC1 and 11 [3%] vs eight [5%] in UC2; adverse events leading to discontinuation six [2%] vs 14 [9%] in UC1 and six [2%] vs nine [5%] in UC2). In UC3, the most frequently reported adverse events (≥5%) were worsening of ulcerative colitis (19 [13%] of 148 in the upadacitinib 15 mg group vs 11 [7%] of 154 in the upadacitinib 30 mg group vs 45 [30%] of 149 in the placebo group), nasopharyngitis (18 [12%] vs 22 [14%] vs 15 [10%]), creatine phosphokinase elevation (nine [6%] vs 13 [8%] vs three [2%]), arthralgia (nine [6%] vs five [3%] vs 15 [10%]), and upper respiratory tract infection (seven [5%] vs nine [6%] vs six [4%]). The proportion of serious adverse events (ten [7%] vs nine [6%] vs 19 [13%]) and adverse events leading to discontinuation (six [4%] vs ten [6%] vs 17 [11%]) was lower in both upadacitinib groups than in the placebo group. Events of cancer, adjudicated major adverse cardiac events, or venous thromboembolism were reported infrequently. There were no treatment-related deaths. Upadacitinib demonstrated a positive efficacy and safety profile and could be an effective treatment option for patients with moderately to severely active ulcerative colitis. AbbVie.

BACKGROUND: Serum tumour necrosis factor-alpha (TNF-α) levels correlate negatively with hepatitis C virus (HCV) antiviral response. OBJECTIVES: To test the hypothesis that a single infliximab induction dose would positively influence on-treatment virological response and sustained virological response (SVR). METHODS: The present study was a phase IIIB, randomized, prospective, open-label pilot trial conducted at eight Canadian sites. Treatment-naive HCV genotype 1-infected patients 18 to 65 years of age with high serum TNF-α values (>300 pg/mL) were randomly assigned to receive a single pretreatment induction infliximab infusion (5 mg/kg) seven days before antiviral therapy (arm A) or no pretreatment (arm B). All patients received pegylated interferon α2b (1.5 μg/kg/week) plus weight-based ribavirin (800 mg/day to 1400 mg/day) for up to 48 weeks. RESULTS: Eighty-five patients (arm A [n=41], arm B [n=44]; 70% male) received pegylated interferon α2b. The mean age (48.1 years), race (81% white) and METAVIR fibrosis stage (F0–2 = 79%, F3–4 = 21%) were similar between groups. Infliximab was well tolerated without attributable severe adverse events; 56.5% completed the study (arm A [n=21], arm B [n=27]). Most discontinuations were due to virological failure at weeks 12 (n=20 [23.5%]) and 24 (n=7 [8.2%]) and did not differ according to group. Numerically lower proportions of infliximab recipients achieved rapid virological response (19.5% versus 36.4%), complete early virological response (43.9% versus 59.1%) and SVR (34.1% versus 52.3%). However, between-group differences did not reach statistical significance. No differences in adverse event profile or laboratory measures were noted. CONCLUSION: A single infliximab dose before pegylated-interferon α2b and ribavirin therapy did not result in greater viral decline during the first 12 weeks of HCV therapy or improved SVR.

Untreated, chronic hepatitis C virus (HCV) infection may lead to progressive liver damage, which can be mitigated by successful treatment. This integrated analysis reports the safety, efficacy, and pharmacokinetics (PK) of the ribavirin-free, direct-acting, antiviral, fixed-dose combination of glecaprevir/pibrentasvir (G/P) in patients with chronic HCV genotype 1-6 infections and compensated liver disease, including patients with chronic kidney disease stages 4 or 5 (CKD 4/5). Data from 9 Phase II and III clinical trials, assessing the efficacy and safety of G/P treatment for 8-16 weeks, were included. The presence of cirrhosis was determined at screening using a liver biopsy, transient elastography, or serum biomarkers. The objectives were to evaluate safety, the rate of sustained virologic response at post-treatment week 12 (SVR12), and steady-state PK by cirrhosis status. Among 2369 patients, 308 (13%) were Child-Pugh Class A, including 20 with CKD 4/5. Overall, <1% of patients experienced an adverse event (AE) that led to G/P discontinuation or G/P-related serious AEs (SAEs). The most common AEs were headache and fatigue, occurring at similar frequencies with and without cirrhosis. SAEs were more common in patients with CKD 4/5, but all were unrelated to G/P. There were no cases of drug-induced liver injury or clinically relevant hepatic decompensation. SVR12 rates were 96.4% (297/308) with compensated cirrhosis and 97.5% (2010/2061) without cirrhosis. PK analysis demonstrated a 2.2-fold increase in glecaprevir exposure, but not pibrentasvir exposure, in patients with compensated cirrhosis. G/P was safe and efficacious in patients with compensated liver disease, including those with CKD 4/5. NCT02243280, NCT02243293, NCT02604017, NCT02640482, NCT02640157, NCT02636595, NCT02642432, NCT02651194, and NCT02446717.

Background. Patients chronically infected with genotype 3 hepatitis C virus (HCV) have faster disease progression and are less responsive to current direct-acting antiviral regimens than patients infected with other genotypes. We conducted an open-label trial to evaluate the safety, tolerability, and efficacy of ledipasvir and sofosbuvir plus ribavirin in patients with genotype 3 HCV infection. Methods. We enrolled treatment-naive patients with and without compensated cirrhosis at 15 sites in Canada. All patients were treated with ledipasvir-sofosbuvir (90 mg and 400 mg) plus weight-based ribavirin for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Secondary endpoints included evaluation of baseline and treatment-emergent drug resistance. Results. Of the 111 patients enrolled, 105 (95%) had subtype 3a HCV and 39 (35%) had compensated cirrhosis. SVR12 was achieved by 99 of 111 patients (89%; 95% confidence interval, 82%–94%). Of the 39 patients with cirrhosis, 31 (79%) achieved SVR12, compared with 68 of 72 (94%) patients without cirrhosis. No treatment-emergent resistance mutations occurred in those who failed treatment. One patient discontinued treatment due to liver cancer and died 22 days after treatment discontinuation. The most common adverse events were fatigue (51%), headache (36%), and nausea (23%). Conclusions. In this multicenter trial involving treatment-naive patients with genotype 3 HCV, 12 weeks of ledipasvir-sofosbuvir provided a high level of SVR in those without cirrhosis. Clinical Trials Registration. NCT02413593.

We report an outbreak of trichinosis from the consumption of locally processed, cold smoked wild boar meat of a domestically reared animal from a farm in Dufferin County, Ontario. Between January and March 1993, 24 cases of trichinosis were identified and of these, 21 patients were symptomatic. The most common symptoms were myalgia (75%), weakness (75%), fever (71%) and periorbital edema (67%). Eosinophilia and elevated creatine phosphokinase levels were noted in 86% and 89% of patients respectively. Trichinelh serology was positive in 55%. Two patients were hospitalized, one with severe diarrhoea and another with myalgia and fever. Several patients appeared to improve temporarily after treatment with albendazole. This outbreak reminds us that although trichinosis is rare in Ontario, physicians must maintain a high index of suspicion for the disease. To prevent further outbreaks, the Ontario Government has instituted new guidelines for the processing of all wild boar meat. Nous rapportons ici une eclosión de trichinose en Ontario associée à la consommation de viande froide fumée localement et provenant d'un sanglier sauvage gardé en élevage sur une ferme du comté de Dufferin. Entre janvier et mars 1993, 24 cas de trichinose furent identifiés, dont 21 patients symptomatiques. Les symptômes les plus fréquents étaient : myalgies (75 %), faiblesse (75 %), fièvre (71 %) et oedème péri-orbital (67 %). L'éosinophilie et une élévation des niveaux de créatinine-phosphokinase étaient présentes chez 86 % et 89 % des patients respectivement. La sérologie pour trichinelh était positive dans 55 % des cas. Deux patients furent hospitalisés, un présentant des diarrhées sévères et l'autre des myalgies et de la fièvre. Plusieurs patients notèrent une amélioration temporaire après un traitement avec l'albendazole. Cette eclosión nous rappelle que, bien que la trichinose soit rare en Ontario, les médecins doivent continuer à l'inclure dans leurs diagnostics différentiels. Pour prévenir d'autres éclosions, les autorités sanitaires ontariennes ont mis en place de nouvelles lignes directrices pour le traitement de toute viande de sanglier sauvage.