Efficacy and safety of filgotinib as induction and maintenance therapy for Crohn's disease (DIVERSITY): a phase 3, double-blind, randomised, placebo-controlled trial.
There is a need for efficacious therapies for patients with Crohn's disease that are better tolerated and more durable than available treatments. We aimed to evaluate the efficacy and safety of filgotinib, an oral Janus kinase 1 preferential inhibitor, for treating Crohn's disease.
This phase 3, double-blind, randomised, placebo-controlled trial was conducted in 371 centres in 39 countries. Eligible patients were aged 18-75 years with moderately to severely active Crohn's disease for at least 3 months before enrolment. Patients were enrolled into one of two induction studies on the basis of their experience with biological agents (induction study A included biologic-naive and later biologic-experienced patients and induction study B included biologic-experienced patients). In both induction studies, patients were randomly assigned (1:1:1), using an interactive web response system, to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once daily for 11 weeks. Patients who received filgotinib and had two-item patient-reported outcome (PRO2) clinical remission or an endoscopic response at week 10 were re-randomised (2:1) to receive their induction dose or placebo orally, once daily to the end of week 58 in the maintenance study. Co-primary endpoints were PRO2 clinical remission and an endoscopic response at week 10 (induction studies) and week 58 (maintenance study). PRO2 clinical remission was defined as an abdominal pain subscore of not more than 1 and a liquid or very soft stool frequency subscore of not more than 3 (from eDiary data) and endoscopic response was defined as a reduction of at least 50% in Simple Endoscopic Score for Crohn's disease from induction baseline (from central reading of endoscopy). For the induction studies, efficacy was assessed in all randomly assigned patients who received at least one dose of study drug. For the maintenance study, efficacy was assessed in all patients from either filgotinib treatment group in the induction studies who reached PRO2 clinical remission or an endoscopic response at week 10, and who were re-randomised and received at least one dose of study drug in the maintenance study. Patients who received placebo throughout the induction and maintenance studies were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least one dose of study drug. This trial is complete and is registered with ClinicalTrials.gov, NCT02914561.
Between Oct 31, 2016, and Nov 11, 2022, 2634 patients were screened, of whom 1372 were enrolled (induction study A: n=707, induction study B: n=665, and maintenance study: n=481). There were 346 (49%) women and 358 (51%) men in induction study A, 356 (54%) women and 303 (46%) men in induction study B, and 242 women (51%) and 236 men (49%) in the maintenance study. Significantly more patients had PRO2 clinical remission at week 10 with filgotinib 200 mg than with placebo in induction study B (29·7% vs 17·9%, difference 11·9%; 95% CI 3·7 to 20·2, p=0·0039) but not induction study A (32·9% vs 25·7%, 6·9%; -1·4 to 15·2, p=0·0963); there was no significant difference for endoscopic response (induction study A: 23·9% vs 18·1%, difference 5·5%; 95% CI -2·0 to 12·9, p=0·1365; induction study B: 11·9% vs 11·4%, 0·1%; -6·5 to 6·6, p=0·9797). At week 58, both co-primary endpoints were reported in greater proportions of patients who received filgotinib 200 mg than in those who received placebo (PRO2 clinical remission: 43·8% vs 26·4%, difference 16·8%; 95% CI 2·0 to 31·6, p=0·0382; endoscopic response: 30·4% vs 9·4%, difference 20·6%; 95% CI 8·2 to 33·1, p=0·0038). Co-primary endpoints were not met for filgotinib 100 mg in any study. In the induction studies, the most frequently reported treatment-emergent adverse events (TEAEs; ≥5% of patients in any group) were abdominal pain; arthralgia; an exacerbation, flare, or worsening of Crohn's disease; headache; nasopharyngitis; nausea; and pyrexia. In the maintenance study, the most frequently reported TEAEs (≥5% of patients in any filgotinib or associated placebo group) were those reported in the induction studies (except for headache) and abdominal distension, upper abdominal pain, anaemia, and flatulence. Serious TEAEs were reported in 49 patients in induction study A (18 [8%]) of 222 patients in the filgotinib 200 mg group, 16 [7%] of 245 patients in the filgotinib 100 mg group, and 15 [6%] of 237 patients in the placebo group), 81 patients in induction study B (19 [9%] of 202 patients in the filgotinib 200 mg group, 36 [16%] of 228 patients in the filgotinib 100 mg group, and 26 [11%] of 229 patients in the placebo group), and 49 patients in the maintenance study (13 [11%] of 118 patients in the filgotinib 200 mg-filgotinib 200 mg group, five [9%] of 56 patients in the filgotinib 200 mg-placebo group, 14 [13%] of 104 patients in the filgotinib 100 mg-filgotinib 100 mg group, three [5%] of 55 patients in the filgotinib 100 mg-placebo group, and 14 [10%] of 145 patients in the placebo-placebo group). No deaths were reported during the induction and maintenance studies.
Filgotinib 200 mg did not meet the co-primary endpoints of clinical remission and an endoscopic response at week 10, but did meet the co-primary endpoints at week 58. Filgotinib treatment was well tolerated, and no new safety signals were reported.
Galapagos.
Vermeire S
，Schreiber S
，Rubin DT
，D'Haens G
，Reinisch W
，Watanabe M
，Mehta R
，Roblin X
，Beales I
，Gietka P
，Hibi T
，Hospodarskyy I
，Ritter T
，Genovese MC
，Kwon P
，Santermans E
，Le Brun FO
，Barron R
，Masior T
，Danese S
... -
《The Lancet Gastroenterology & Hepatology》
Comparative analysis of C-Reactive protein levels among Non-comorbid, Comorbid, and Multimorbid Hospitalized COVID-19 patients.
C-reactive protein (CRP) is one of the most commonly monitored inflammatory markers in patients with COVID-19 to gain insight into the inflammation level in the body and to adopt effective disease management and therapeutic strategies. COVID-19 is now less prevalent, and the study of CRP as a biomarker of inflammation still needs deeper understanding, particularly in understanding its role among patients with comorbidities, which are known to influence inflammatory responses and increase the risk of severe outcomes during acute and chronic infectious diseases. The objective of this study was to evaluate the association of major comorbidities such as ischemic heart diseases, diabetes, chronic kidney disease, hypertension, and lung infections e.g. tuberculosis with serum CRP levels in hospitalized COVID-19 patients.
This study involves a retrospective observational framework to monitor CRP levels among hospitalized COVID-19 patients after getting ethical approval and patient consent. The information on underlying health conditions or comorbidities and age was collected from the patient data files. The requirement of ventilation, ICU admission, mortality & survival, and CRP levels were monitored based on their daily updates in the data file. Furthermore, the association of CRP levels was evaluated with disease severity and mortality.
In this study 618 out of 750 hospitalized COVID-19 patients, of which 62.6% were male and 37.4% were female, the levels of serum CRP were significantly influenced by age and comorbidities. No case of hospitalization was observed in children (≤ 14 years) during the study period, while 38.3% of patients belonged to the old age group (≥ 65 years). Comorbidity status varied, with 36.1% of patients without having any comorbidities, 27.8% with one, 23.6% with two, and 12.5% with three or more comorbidities. Descriptive statistics revealed that the CRP levels in the study population averaged 88.92 mg/L (SD = 63.95), ranging from < 1 mg/L to 900 mg/L, with significant variations observed across different comorbidities and age groups. CRP levels, analyzed by the Kruskal-Wallis test, showed significant variations in different age groups of COVID-19 patients (χ² = 66.741, df = 3, p < 0.001). Moreover, pairwise comparisons showed considerable differences between young and middle-aged groups (Z = -2.724, p < 0.01) and young and old age groups of COVID-19 patients (Z = -3.970, p < 0.001). The most prevalent comorbidities observed in COVID-19 patients in this study were hypertension (42.1%), diabetes (33.8%), ischemic heart disease (16.5%), asthma (11.2%), chronic kidney disease (7.9%) and Tuberculosis (1.9%). The CRP levels fluctuate and also significantly differ among different comorbidities. COVID-19 patients with diabetes were observed to have higher CRP levels than non-diabetics (mean CRP: 126.96 mg/L vs. 88.92 mg/L, Z = -5.724, p < 0.001), and those with hypertension also encountered elevated CRP (mean CRP: 355.37 vs. 276.19 mg/L, Z = -5.447, p < 0.001). Similar tendencies were detected in COVID-19 patients with ischemic heart disease (mean CRP: 385.43 mg/L, Z = -4.704, p < 0.001), chronic kidney disease (mean CRP: 412.37 mg/L, Z = -4.206, p < 0.001) as well as with tuberculosis (mean CRP: 458.08 mg/L, Z = -2.914, p < 0.01). CRP levels on days 1 and 3 of hospitalization showed a decline (88.92 mg/L to 67.89 mg/L), representative of a response to treatment to reduce the inflammation in the body. Furthermore, high levels of CRP were significantly associated with a high requirement of non-invasive ventilation (mean CRP: 110.80 mg/L vs. 76.82 mg/L, p < 0.05), mechanical ventilation (mean CRP: 134.46 mg/L vs. 77.25 mg/L, p < 0.05) and ICU admission (mean CRP: 126.96 mg/L vs. 72.79 mg/L, p < 0.05). The Cox regression analysis showed that there is a considerable association of CRP level with the expected length of hospitalization, each 1-unit increase in CRP levels was associated with a 0.6% increase in extended stay risk (hazard ratio = 1.006, 95% CI: 1.004-1.008, p < 0.001). Furthermore, the logistic regression analysis performed on CRP levels that was monitored on the first day of hospitalization, revealed that there was a 2.7% increase in mortality odds with each unit increase in CRP (odds ratio = 1.027, 95% CI: 1.022-1.033, p < 0.001), which suggest CRP as a potential mortality predictor.
Elevated CRP levels in COVID-19 patients with comorbidities like diabetes, hypertension, ischemic heart disease, and chronic kidney disease were strongly associated with increased disease severity, including higher ventilation requirements and mortality. Patients with these comorbidities showed significantly higher CRP levels, which correlated with worse outcomes, including ICU admissions and prolonged hospital stays, emphasizing the importance of CRP as a predictor for severe complications in patients with infectious diseases along with one or more comorbidities.
Shoukat M
，Khan H
，Nazish M
，Rehman A
，Raashid S
，Ahmed S
，Munir W
，Alrefaei AF
，Umair M
，Bin Abid MO
，Akhtar N
，Zaman W
，Badshah M
... -
《BMC INFECTIOUS DISEASES》
Randomized, Double-Blind, Placebo-Controlled Trial on the Efficacy, Safety and Tolerability of Modified-Release Methylphenidate (MPH-MR) in Chinese Children and Adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD).
The efficacy and safety of modified-release methylphenidate (MPH-MR) in the treatment of attention-deficit/hyperactivity disorder (ADHD) have been shown in both pediatric and adult Caucasian patients. The objective of this study was to assess the efficacy and safety of MPH-MR in Chinese children and adolescents with ADHD.
MICCA was a randomized, double-blind, placebo-controlled trial conducted at 19 sites in China from September 2018 to July 2021. The study enrolled children and adolescents aged 6 to < 18 years with a primary diagnosis of ADHD according to the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5). Patients were randomized 1:1 to once-daily MPH-MR (10-60 mg) or placebo. The study included an up-titration phase of up to 5 weeks and a dose maintenance phase of 4 weeks. The primary efficacy endpoint was the change in the ADHD Rating Scale-IV (ADHD-RS-IV) total score from baseline to the end of the maintenance phase (EoM). Secondary endpoints included the change from baseline to EoM in Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) total score, and Clinical Global Impression-Improvement (CGI-I) scores at EoM. Safety assessments included treatment-emergent adverse events (TEAEs) and vital signs.
A total of 221 patients were randomized (MPH-MR: n = 110; placebo: n = 111). The change in the ADHD-RS-IV total score from baseline to EoM was significantly greater for MPH-MR versus placebo, with a least squares (LS) mean (95% confidence interval [CI]) treatment difference of - 4.6 (- 6.92, - 2.30) (p < 0.001). The mean (95% CI) treatment difference for the WFIRS-P total score change from baseline to EoM also significantly favored MPH-MR over placebo (- 6.46 [- 10.57, - 2.34]; p = 0.002). The CGI-I score at EoM was significantly lower in the MPH-MR group compared to the placebo group (2.2 vs 2.5; p = 0.002). Treatment-emergent adverse events were reported for 74 (67.3%) patients in the MPH-MR group and 55 (49.1%) patients in the placebo group. Most TEAEs were mild to moderate in severity. The most common TEAEs for MPH-MR were decreased appetite, nausea and upper respiratory tract infection. Treatment-emergent adverse events leading to study drug discontinuation/study withdrawal were reported in 4 (3.6%) patients in the MPH-MR group and 1 (0.9%) patient in the placebo group. No clinically relevant changes in vital signs were observed during the study.
Modified-release methylphenidate was superior to placebo in improving ADHD symptoms and functioning in Chinese pediatric patients with ADHD. Modified-release methylphenidate had a good safety and tolerability profile. Trial Registration http://www.chinadrugtrials.org.cn/ Identifier: CTR20180056 (registered on 21 May 2018).
Zheng Y
，Liu H
，Wang X
，Li H
，Ruhmann M
，Mayer A
，Dangel O
，Ammer R
... -
《-》
ResearchGate
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钛学术
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