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 & Aims
Introduction of highly efficacious pan‐genotypic therapies for hepatitis C virus (HCV) infection has made the elimination of the disease an attainable goal. This study assessed ...progress made in 45 high‐income countries towards meeting the World Health Organization's targets for HCV elimination by 2030.
Methods
A Markov model developed to forecast annual HCV‐infected population was populated with demographic and epidemiological inputs, with historical incidence calibrated to reported prevalence of chronic HCV for each country. Future incidence was assumed to be a linear function of overall prevalence (or prevalence of minimal fibrosis in countries with treatment restrictions). 2017 levels of diagnosis and treatment were assumed constant in the future. The analysis estimated the year countries would meet HCV elimination targets for 80% reduction in incidence, 65% reduction in liver‐related deaths, 90% diagnosis coverage and 80% treatment among the treatment‐eligible population.
Results
Of the 45 countries analyzed, nine (Australia, France, Iceland, Italy, Japan, South Korea, Spain, Switzerland and the United Kingdom) are on track towards meeting the HCV elimination targets by 2030. While Austria, Germany and Malta could also reach the targets with expanded screening efforts, 30 countries are not projected to eliminate HCV before 2050. Incidence was the most difficult target to achieve, followed by liver‐related deaths.
Conclusions
Even with introduction of curative therapies, 80% of high‐income countries are not on track to meet HCV elimination targets by 2030, and 67% are off track by at least 20 years. Immediate action to improve HCV screening and treatment is needed globally to make HCV elimination attainable.
SERENE UC (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Ulcerative Colitis) evaluated the efficacy of higher adalimumab induction ...and maintenance dose regimens in patients with ulcerative colitis.
This phase 3, double-blind, randomized trial included induction and maintenance studies, with a main study (ex-Japan) and Japan substudy. Eligible patients (18–75 years, full Mayo score 6–12, centrally read endoscopy subscore 2–3) were randomized 3:2 to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3) or standard induction regimen (160 mg at week 0 and 80 mg at week 2); all received 40 mg at weeks 4 and 6. At week 8, all patients were rerandomized 2:2:1 (main study) to 40 mg every week (ew), 40 mg every other week (eow), or exploratory therapeutic drug monitoring; or 1:1 (Japan substudy) to 40 mg ew or 40 mg eow maintenance regimens.
In the main study, 13.3% vs 10.9% of patients receiving the higher induction regimen vs standard induction regimen achieved clinical remission (full Mayo score ≤2 with no subscore >1) at week 8 (induction primary end point; P = .265); among week-8 responders, 39.5% vs 29.0% receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (maintenance primary end point; P = .069). In the integrated (main + Japan) population, 41.1% vs 30.1% of week-8 responders receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (nominal P = .045). Safety profiles were comparable between dosing regimens.
Although primary end points were not met, a >10% absolute difference in clinical remission was demonstrated with higher adalimumab maintenance dosing. Higher dosing regimens were generally well tolerated and consistent with the known safety profile of adalimumab in ulcerative colitis. ClinicalTrials.gov, Number: NCT002209456.
SERENE UC confirms adalimumab is safe and effective in ulcerative colitis. Higher and standard induction dosing were similar and clinical remission was more frequently achieved with higher vs standard maintenance dosing.
Introduction
Although hepatitis C virus (HCV) infection remains a major clinical, economic, and societal burden, the development of curative antiviral therapy may accelerate the path toward ...elimination. This analysis assessed the progress of United States (US) states towards achieving the World Health Organization’s (WHO) 2030 HCV elimination targets for incidence, mortality, diagnosis, and treatment.
Methods
A previously published Markov model was used to simulate HCV progression over time to estimate the path to HCV elimination in each state based on prevalence, annual treatment, and diagnosis inputs from two large US laboratory datasets from January 2013 to December 2017. State-specific fibrosis stage restrictions on treatment in 2017 were included. The model estimated the year individual states would meet the WHO targets for diagnosing 90% of the HCV-infected population, treating 80% of the eligible population, reducing new HCV infections by 80%, and reducing HCV-related deaths by 65%. The minimum number of annual treatments needed between 2020 and 2030 to achieve the WHO treatment target was also calculated.
Results
Overall, the USA is projected to achieve HCV elimination by 2037, with individual targets related to mortality, diagnosis, treatment, and incidence being achieved by 2020, 2027, 2033, and 2037, respectively. Three states (Connecticut, South Carolina, and Washington) are on track to meet all four elimination targets by 2030, and 18 states are not expected to meet these targets before 2040. The estimated annual number of treatments required during 2020–2030 nationally to reach the WHO treatment target is 173,514.
Conclusion
With the exception of three states, the USA is not on target to meet the WHO 2030 elimination targets and 35% are off track by 10 years or more. Strategies must be implemented to reduce overall prevalence by preventing new infections, increasing rates of screening, improving linkage to care, and implementing unfettered access to curative therapy.
Background
Due to wide-ranging impacts of Ulcerative Colitis (UC), regulatory authorities emphasize the importance of including validated patient-reported symptom severity measures in clinical ...trials.
Aim
To describe the development and validation of the Ulcerative Colitis-Symptom Questionnaire (UC-SQ).
Methods
The UC-SQ was developed in a qualitative study involving a targeted literature review, semi-structured concept elicitation interviews, and combined concept elicitation/cognitive interviews. Measurement properties, including item-level analyses, factor structure, reliability, validity, responsiveness, and clinically meaningful change were evaluated using data from a phase 2b, randomized trial in adults with UC (
N
= 113).
Results
Fourteen symptom concepts were elicited across 22 interviews, with saturation at the fifth interview. Twenty-two items were unmodified as cognitive interview participants interpreted underlying concepts correctly. Instructions were clear and items were relevant, with appropriate response options and recall periods. Reduction to 17 items was completed prior to psychometric testing. Two items (joint pain/constipation) did not contribute to reliability in initial testing and were included as non-scored items. The 15-item UC-SQ showed evidence of internal consistency (
α
= 0.86) and test–retest reliability (intraclass correlation coefficient = 0.88). The UC-SQ discriminated by disease severity as defined by Mayo and Inflammatory Bowel Disease Questionnaire scores (
p
< 0.0001). Convergent validity was supported by strong correlations with criterion measures. The UC-SQ was responsive in patients indicating change in other measures. A 10-point decrease from baseline indicated within-patient meaningful improvement.
Conclusions
The UC-SQ is reliable, valid and responsive, with a 10-point improvement estimating within-patient clinically meaningful improvement. The tool is fit-for-purpose as a key endpoint in pivotal UC trials.
Abstract
Background and Aims
Bowel urgency and abdominal pain are impactful, yet under-appreciated ulcerative colitis symptoms and not commonly assessed in clinical trials. We evaluated how these ...symptoms may improve with upadacitinib treatment and correlate with clinical and health-related quality of life HRQOL outcomes in the phase 2b U-ACHIEVE study.
Methods
Patients aged 18–75 years, with moderately to severely active ulcerative colitis, were randomised to receive placebo or upadacitinib (7.5, 15, 30, or 45 mg once daily QD). Bowel urgency and abdominal pain were evaluated at baseline and Weeks 2, 4, 6, and 8. Week 8 correlations were evaluated between bowel urgency/abdominal pain with clinical Mayo subscores and high-sensitivity C-reactive protein and faecal calprotectin measurements and HRQOL outcomes Inflammatory Bowel Disease Questionnaire and 36-Item Short Form Health Survey scores.
Results
A greater proportion of patients n = 250 reported no bowel urgency and less abdominal pain with upadacitinib treatment compared with placebo, with improvements observed as early as 2 weeks. At Week 8, patients receiving the 45-mg QD dose had the greatest improvements versus placebo, with 46% reporting no bowel urgency vs 9%; p ≤ 0.001 and 38% reporting no abdominal pain vs 13%; p = 0.015. At Week 8, moderate correlations were found between bowel urgency or abdominal pain and most clinical and HRQOL outcomes.
Conclusions
Induction treatment with upadacitinib demonstrated significant reductions in bowel urgency and abdominal pain compared with placebo. These symptoms also correlate to clinical and HRQOL outcomes, supporting their use to monitor disease severity and other treatment outcomes.
This paper analyzes the spatio-temporal variations, and exceedances of the PM2.5 concentrations in Northwestern South America at different scales to assess the implemented policies and identify the ...involved phenomena. Through reanalysis and ground-based data, we found that high PM2.5 levels in most cities of the region are caused by wildfires and local emissions, including the capital cities of Venezuela, Ecuador, Colombia, and Panamá. In-situ measurements suggest that the majority of the cities comply with the local but not with the WHO guidelines, indicating that local annual limits should be more restrictive. Two peaks in the daily variations of PM2.5 (related to vehicle emissions) and also a steeper decrease around noon (associated with an increase in wind speed and in the boundary layer height) were identified. The trend-analysis shows that Bogotá and Medellín have a decreasing PM2.5 annual-trend (between −0.8μgm−3 and −1.7μgm−3) that corresponds to effective policies. In contrast, Cali has a positive annual-trend (0.8μgm−3) most likely because of Short-Range Transport produced by a northerly-flow from a highly polluted neighboring city, which also affects Cali's PM2.5 diurnal cycle, or by local-dynamics. The exceedances show that the policies are working on an annual but not at a daily time-scale. These results serve as a first input for additional studies, with the aim of gaining a better understanding of the contaminant before adapting current policies or implementing new policies and measures that need to include a joint international, regional, and inter-city efforts regarding pollution transport.
Display omitted
•PM2.5 monthly means have declined over four of five cities studied during 2014–2019.•Wild-control fires and pollution advection between cities decrease air quality.•Mobile emissions, wind patterns, and the boundary layer govern the PM2.5 diurnal cycle.•Days exceeding local/WHO limits are not declining, yet yearly policies seem effective.•Joint international and inter-city efforts are needed to design air quality policies.
Patients with moderately to severely active ulcerative colitis have an increasing number of advanced therapy options including several biologics and Janus kinase inhibitors. Though data on efficacy ...and safety of these advanced therapies are available, less is known about the potential economic implications of their utilization in Japan. We evaluated the relative value of these advanced therapies in Japan using a locally developed cost per responder model.
A model was developed using relevant clinical endpoints and treatment costs to calculate cost per responder of all advanced therapies used for moderately to severely active ulcerative colitis treatment in Japan. Cost per responder was assessed in biologic-naïve and biologic-exposed populations, respectively. The model incorporated induction and maintenance therapy pathways as patients progressed through based on efficacy rates (clinical response, clinical remission and endoscopic improvement). Total costs for induction and maintenance included: drug acquisition, drug administration and serious adverse event management (as necessary) for responders, with additional rescue treatment cost only for non-responders.
Upadacitinib showed lower cost per clinical response and cost per clinical remission across both biologic-naïve and biologic-exposed populations with only one exemption in cost per clinical remission in biologic-naïve population. In addition, upadacitinib demonstrated lower cost per endoscopic improvement in both populations. Janus kinase inhibitors outperformed with lower cost per responder than other mediations across all outcomes and patient populations with the exception of tofacitinib for clinical remission in biologic-exposed UC population.
Comparative data used in this analysis have been derived from network meta-analysis, not from direct comparison.
The results of this cost per responder analysis suggest upadacitinib is a cost-effective option for the first- and second-line treatment of moderately to severely active ulcerative colitis in Japan.
Background
We evaluated the clinical relevance of achieving histologic endoscopic mucosal improvement (HEMI) and the more stringent target of histologic endoscopic mucosal remission (HEMR) in the ...phase 3 maintenance trial of upadacitinib for moderately to severely active ulcerative colitis.
Methods
Clinical and patient-reported outcomes were assessed in patients with clinical response after 8- or 16-week upadacitinib induction who received 52-week upadacitinib maintenance treatment. Cross-sectional and predictive analyses evaluated the relationship between HEMR or HEMI at Week 8/16 and Week 52, respectively, and outcomes at Week 52. Adjusted odds ratios (aOR) were derived from logistic regressions for patients achieving HEMR or HEMI without HEMR versus those not achieving HEMI.
Results
Cross-sectional analyses showed that patients with HEMR had greater odds of achieving all clinical and patient-reported outcomes at Week 52 than those not achieving HEMI. In predictive analyses, patients with HEMR at Week 8/16 had significantly greater odds of achieving clinical remission (aOR = 3.6,
p
= 0.001) and endoscopic remission (aOR = 3.9,
p
< 0.001) at Week 52 than patients not achieving HEMI and HEMR. For patients achieving HEMI without HEMR, these odds were lower: clinical remission (aOR = 3.2,
p
< 0.001) and endoscopic remission (aOR = 2.4,
p
= 0.010). The odds of achieving clinically meaningful improvements in most patient-reported outcomes were directionally similar between HEMI and HEMR, but not statistically different to patients not achieving HEMI. No hospitalizations or surgeries were observed in patients with HEMR at Week 52.
Conclusions
Achievement of HEMR or HEMI is clinically relevant with HEMR being associated with greater likelihood of improvement in long-term clinical and patient-reported outcomes.
https://www.clinicaltrials.gov
NCT02819635.
ABSTRACT
BACKGROUND & AIMS
Elimination of HCV by 2030, as defined by the World Health Organization (WHO), is attainable with the availability of highly efficacious therapies. This study reports ...progress made in the timing of HCV elimination in 45 high‐income countries between 2017 and 2019.
METHODS
Disease progression models of HCV infection for each country were updated with latest data on chronic HCV prevalence, and annual diagnosis and treatment levels, assumed to remain constant in the future. Modelled outcomes were analysed to determine the year in which each country would meet the WHO 2030 elimination targets.
RESULTS
Of the 45 countries studied, 11 (Australia, Canada, France, Germany, Iceland, Italy, Japan, Spain, Sweden, Switzerland, and United Kingdom) are on track to meet WHO's elimination targets by 2030; five (Austria, Malta, Netherlands, New Zealand, and South Korea) by 2040; and two (Saudi Arabia and Taiwan) by 2050. The remaining 27 countries are not expected to achieve elimination before 2050. Compared to progress in 2017, South Korea is no longer on track to eliminate HCV by 2030, three (Canada, Germany, and Sweden) are now on track, and most countries (30) saw no change.
CONCLUSIONS
Assuming high‐income countries will maintain current levels of diagnosis and treatment, only 24% are on track to eliminate HCV by 2030, and 60% are off track by at least 20 years. If current levels of diagnosis and treatment continue falling, achieving WHO's 2030 targets will be more challenging. With less than ten years remaining, screening and treatment expansion is crucial to meet WHO's HCV elimination targets.
PDF
