Targeting Remission in Moderate-to-Severe Crohn's Disease.
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ABSTRACT:
SUBMITTER: Kish T
PROVIDER: S-EPMC5969213 | biostudies-other | 2018 Jun
REPOSITORIES: biostudies-other
Publications
Targeting Remission in Moderate-to-Severe Crohn's Disease.
P & T : a peer-reviewed journal for formulary management 20180601 6
Therapeutic options in development for the treatment of Crohn's disease represent a broad range of approaches to this complex disease. This active pipeline contains a combination of both small-molecule entities and targeted monoclonal antibodies. ...[more]
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Project description:BackgroundWe summarized the protocol-specified corticosteroid tapering regimens in clinical trials of moderate-severe ulcerative colitis (UC) and Crohn's disease (CD) and calculated differences in rates of clinical remission vs corticosteroid-free clinical remission (CSF-CR).MethodsThrough a systematic literature review through February 28, 2019, we identified 16 randomized controlled trials (RCTs) of biologics or small molecules in patients with moderate-severe UC or CD who reported CSF-CR as an outcome. We estimated the relative risk and 95% confidence interval of achieving CSF-CR vs overall clinical remission in patients treated with active intervention or placebo through random-effects meta-analysis.ResultsAcross trials of UC (11 trials) and CD (5 trials), a median of 53% and 49% of participants were on corticosteroids at the time of trial entry, respectively. Participants were allowed to enter trials at a median corticosteroid dose (range) of 35 (20-40) mg/d. Doses were kept stable for a median (range) of 8 (5-10) weeks during induction therapy, after which a mandatory and structured taper was implemented, albeit with the investigators' discretion depending on clinical status. Pooled rates of CSF-CR in patients with UC and CD treated with placebo were 9.7% and 19.1%, respectively. In UC and CD trials, the rate of CSF-CR was 24% and 18% lower than the rate of overall clinical remission, respectively.ConclusionsProtocol-specified corticosteroid tapering regimens vary across trials. These findings will help to inform the design and interpretation of future clinical trials and highlight the need for standardization.
| S-EPMC8127062 | biostudies-literature
Project description:BackgroundCrohn's disease (CD) treatments and associated adverse events (AEs) can be burdensome for patients. However, specific values which quantify the impact on health-related quality of life (HRQL) for economic evaluation are lacking.ObjectivesThis study aimed to elicit health utility values for AEs related to biologic treatment and surgical complications for CD in the UK.MethodsHealth states were developed by literature review and interviews with CD patients (n=6) and gastroenterologists (n=3). Draft health states were validated in cognitive debrief interviews with patients (n=4) and gastroenterologists (n=2). Treatment AEs were described with moderate-severe CD (reference state) and included hypersensitivity, injection site reactions, serious infection, lymphoma, and tuberculosis. Surgical complications were described following bowel surgery (reference state) and included anastomotic leak, wound infection, prolonged ileus/bowel obstruction, and intra-abdominal abscess. Health states were valued by 100 members of the general public who completed background questions, EQ-5D-3L, visual analogue scale rating task and time trade-off (TTO) interviews.ResultsThe mean TTO value for reference states 'moderate to severe CD' and 'bowel surgery' were 0.70 (SD=0.28) and 0.69 (SD=0.28). Participants rated lymphoma as the worst AE/surgical complication state (0.44, SD=0.37), followed by tuberculosis (0.47, SD=0.85) and anastomotic leak (0.48, SD=0.38). Values of other AE/surgical complication states ranged from 0.76 (hypersensitivity) to 0.56 (intra-abdominal abscess).ConclusionsThis study provides utility estimates for AE and surgical complication health states not previously assessed in the context of CD. As new treatments are emerging, it is important to include these influences on quality of life in any economic evaluation of treatments.
| S-EPMC7299447 | biostudies-literature
Project description:OBJECTIVE:To evaluate open-label adalimumab therapy for clinical effectiveness, fistula healing, patient-reported outcomes and safety in Canadian patients with moderate to severe Crohn's disease (CD) who were either naive to or previously exposed to antitumour necrosis factor (anti-TNF) therapy. METHODS:Patients with moderate to severe CD (CD activity index [CDAI] score of greater than 220, or Harvey-Bradshaw index [HBI] of 7 or greater) were eligible. Patients received open-label adalimumab as induction (160 mg and 80 mg subcutaneously [sc]) at weeks 0 and 2, respectively and maintenance (40 mg sc every other week) therapy. At or after eight weeks, patients with flare or nonresponse could have their dosage increased to 40 mg sc weekly. Patients were followed for a minimum of six months or until adalimumab was commercially available in Canada. RESULTS:Of the 304 patients enrolled, 160 were infliximab experienced, while 144 were anti-TNF naive. HBI remission (HBI score of 4 or lower) at week 24 was achieved by 53% of anti-TNF-naive and 36% of infliximab-experienced patients (P<0.01; P<0.001 for both groups for all visits versus baseline). Fistula healing rates at week 12 were 48% for anti-TNF-naive patients, and 26% for infliximab-experienced patients. At week 24, fistula healing rates were significantly greater for the anti-TNF-naive group (60% versus 28%; P<0.01). Improvements in quality of life and work productivity were sustained from week 4 to week 24 for all patients. Serious infections occurred in 2% of patients. CONCLUSIONS:Adalimumab therapy induced and sustained steroidfree remission in both infliximab-experienced and anti-TNF-naive patients with moderate to severe CD. Clinically meaningful rates of fistula healing were also observed. Improvements in patient-reported outcomes were sustained throughout the 24-week study period.
| S-EPMC3186726 | biostudies-literature
Project description:The advent of anti-tumor necrosis factor (TNF)-? therapy has been a major advance in the medical management of Crohn's disease (CD). However, a significant proportion of patients with CD do not respond adequately to treatment with these agents. Primary and secondary nonresponse to anti-TNF? therapy represents a common clinical challenge, and highlights the need for the development of additional medication options for CD. The proinflammatory cytokines interleukin (IL)-12 and IL-23 are thought to play a key role in the pathogenesis of CD, and serve as a potential target for additional biologic therapies. Monoclonal antibodies targeting IL-12/23 have shown efficacy in animal models of colitis, and are currently being studied in Phase III clinical trials of CD. This review focuses on ustekinumab, a fully human immunoglobulin G1 monoclonal antibody, which blocks activity of IL-12 and IL-23 through binding the p40 subunit, and describes the current efficacy and safety data for ustekinumab in patients with CD.
| S-EPMC4041179 | biostudies-other
Project description:Background and aimsThis study evaluated the minimal clinically important short-term improvement in the Modified Multiplier Simple Endoscopic Score for crohn's Disease [MM-SES-CD], a novel modified scoring system of the SES-CD, which reliably predicted 1-year endoscopic remission [ER].MethodsThis post-hoc analysis of two CD clinical trial programmes pooled data of 198 participants with baseline ulcers and SES-CD ≥3, who had baseline, post-induction [8-12 weeks], and 1-year endoscopic assessments. Different cut-off values for endoscopic response were evaluated using receiver operating characteristic [ROC] curves, positive likelihood ratios [PLR], and negative likelihood ratios [NLR]. ER [SES-CD <3] was the binary classifier in all cases. A distribution of cut-offs minimising NLR and maximising PLR was created with 10 000 bootstrapped resamples. An optimal cut-point for low and high probability of 1-year ER was determined based on the maximum Youden Index.ResultsMM-SES-CD ≥40% reduction from baseline was selected as the cut-off maximising PLR and minimising NLR. Among 7.6% [15/198] participants achieving this cut-off post-induction, 1-year ER was 46.7%. One-year ER was 16.9% among those not achieving this cut-off. This threshold predicted 1-year ER with 95.0% (95% confidence interval [CI] 90.4%-97.8%) specificity and a PLR of 3.7 [95% CI 1.4-9.5], which was higher than traditional endoscopic response criteria of SES-CD ≥50% reduction [specificity 62.5%, 95% CI 54.5%-70.0%; PLR 1.9, 95% CI 1.4-2.5]. Lower thresholds of MM-SES-CD reduction also were highly specific for 1-year ER [e.g., MM-SES-CD ≥20% reduction was achieved in 19.7% of patients with 83.1% specificity].ConclusionsIn CD patients, post-induction endoscopic response defined by MM-SES-CD ≥40% reduction from baseline identified patients most likely to achieve 1-year ER.
| S-EPMC9274823 | biostudies-literature
Project description:BackgroundCrohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract, in which the pathogenesis is believed to be partly influenced by the gut microbiome. Probiotics can be used to manipulate the microbiome and have therefore been considered as a potential therapy for CD. There is some evidence that probiotics benefit other gastrointestinal conditions, such as irritable bowel syndrome and ulcerative colitis, but their efficacy in CD is unclear. This is the first update of a Cochrane Review previously published in 2008.ObjectivesTo assess the efficacy and safety of probiotics for the induction of remission in CD.Search methodsThe following electronic databases were searched: MEDLINE (from inception to 6 July 2020), Embase (from inception to 6 July 2020), the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane IBD Review Group Specialised Trials Register, World Health Organization (WHO) International Clinical Trials Registry, and ClinicalTrials.gov.Selection criteriaRandomised controlled trials (RCTs) that compared probiotics with placebo or any other non-probiotic intervention for the induction of remission in CD were eligible for inclusion.Data collection and analysisTwo review authors independently extracted data and assessed the methodological quality of included studies. The primary outcome was clinical remission. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for dichotomous outcomes.Main resultsThere were two studies that met criteria for inclusion. One study from Germany had 11 adult participants with mild-to-moderate CD, who were treated with a one-week course of corticosteroids and antibiotics (ciprofloxacin 500 mg twice daily and metronidazole 250 mg three times a day), followed by randomised assignment to Lactobacillus rhamnosus strain GG (two billion colony-forming units per day) or corn starch placebo. The other study from the United Kingdom (UK) had 35 adult participants with active CD (CDAI score of 150 to 450) randomised to receive a synbiotic treatment (comprised of freeze-dried Bifidobacterium longum and a commercial product) or placebo. The overall risk of bias was low in one study, whereas the other study had unclear risk of bias in relation to random sequence generation, allocation concealment, and blinding. There was no evidence of a difference between the use of probiotics and placebo for the induction of remission in CD (RR 1.06; 95% CI 0.65 to 1.71; 2 studies, 46 participants) after six months. There was no difference in adverse events between probiotics and placebo (RR 2.55; 95% CI 0.11 to 58.60; 2 studies, 46 participants). The evidence for both outcomes was of very low certainty due to risk of bias and imprecision.Authors' conclusionsThe available evidence is very uncertain about the efficacy or safety of probiotics, when compared with placebo, for induction of remission in Crohn's disease. There is a lack of well-designed RCTs in this area and further research is needed.
| S-EPMC7389339 | biostudies-literature
Project description: Not available
| S-EPMC6953260 | biostudies-literature
Project description:IntroductionTo compare the cost-effectiveness of vedolizumab with that of conventional therapy in patients with moderate-to-severe active Crohn's disease (CD) in China.MethodsA decision tree and Markov model were built to predict the lifetime cost and health outcomes in the induction phase and maintenance phase of vedolizumab treatment and conventional therapy (a combination of corticosteroids, immunosuppressants, and aminosalicylates) in adult patients with moderate-to-severe active CD from the perspective of China's healthcare system. Clinical efficacy and health utility were derived from the GEMINI 2 and GEMINI 3 trials and published literature. Costs were mainly obtained from clinical physician surveys in China and are presented in 2020 US dollars. Health outcomes (quality-adjusted life years, QALYs) and costs were discounted at an annual rate of 5%. The incremental cost per QALY gained was used to compare the cost-effectiveness of the two treatments. One-way and probabilistic sensitivity analyses (PSAs) were performed to test the robustness of the model.ResultsThe model predicted more QALYs (9.92 vs 9.00 QALYs) and lower incurred costs ($288,284 vs $309,680) in vedolizumab than in conventional therapy in a mixed population (anti-TNF-naïve and anti-TNF-failure populations) over a lifetime horizon in the base-case analysis. Similar results were observed in the anti-TNF-naïve and anti-TNF-failure subgroups of patients with CD. One-way sensitivity analysis results suggested that health state cost was the most influential factor in the model. The PSA results supported the dominance of vedolizumab in the base-case analysis.ConclusionVedolizumab appears to be a cost-effective strategy option in the treatment of adult patients with moderate-to-severe active CD in China in both anti-TNF-naïve and anti-TNF-failure populations.
| S-EPMC8342392 | biostudies-literature
Project description:BackgroundCrohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract, and immune response modulation is the main treatment strategy to induce remission in active CD. Certolizumab pegol (CZP) is a tumor necrosis factor-alfa (TNF-α) inhibitor which regulates impaired immune response.ObjectivesThe primary objectives were to evaluate the efficacy and safety of CZP for the induction of remission in CD.Search methodsWe searched MEDLINE, Embase, CENTRAL, the Cochrane IBD group specialized register, trials registers and other sources from inception to 28 January 2019. Moreover, we contacted the pharmaceutical company that manufactures CZP.Selection criteriaWe included randomized controlled trials comparing CZP with placebo or no treatment in active CD patients.Data collection and analysisWe used standard Cochrane methodological procedures. The main outcomes selected for GRADE analysis were clinical remission at week 8 (Crohn's Disease Activity Index [CDAI] ≤150), clinical response at week 8 (CDAI reduction ≥ 100 or clinical remission), and serious adverse events. The Mantel-Haenszel random-effects method was applied for the statistical analyses. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI).Main resultsFour studies involving 1485 participants with moderate to severe CD met the inclusion criteria and were used in the meta-analyses. All studies included active CD patients with CDAI ranging from 220 to 450. Most patients were adults over 18 years of age. One study was identified as high risk of bias due to a non-identical placebo while the other studies were judged to be at low risk of bias.CZP (100 mg to 400 mg every 2 to 4 weeks) was shown to be superior to placebo for achieving clinical remission at week 8 (RR 1.36, 95% CI 1.11 to 1.66; moderate certainty evidence). The raw numbers of participants achieving clinical remission at week 8 were 26.9% (225/835) and 19.8% (129/650) in the CZP and the placebo groups, respectively.CZP was shown to be superior to placebo for achieving clinical response at week 8 (RR 1.29, 95% CI 1.09 to 1.53; moderate certainty evidence). In raw numbers, clinical response at week 8 was achieved in 40.2% (336/835) and 30.9% (201/650) of participants in the CZP and the placebo groups, respectively.In raw numbers, serious adverse events were observed in 8.7% (73/835) and 6.2% (40/650) of participants in the CZP and the placebo groups, respectively (RR 1.35, 95% CI 0.93 to 1.97; moderate certainty evidence). Serious adverse events included worsening Crohn's disease, infections, and malignancy.Authors' conclusionsModerate certainty evidence suggests that CZP is effective for induction of clinical remission and clinical response in participants with active CD patients. It is uncertain whether the risk of serious adverse events differs between CZP and placebo as the 95% CI includes the possibility of a small decrease or doubling of events. Future studies are needed to evaluate the long-term efficacy and safety of CZP in CD patients.
| S-EPMC6718195 | biostudies-literature
Project description: Not available
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