Placebo Remission Research Articles

Placebo rates in Crohn’s disease randomized clinical trials: An individual patient data meta-analysis

Understanding placebo rates is critical for efficient clinical trial design. We assessed placebo rates and associated factors using individual patient data (IPD) from Crohn's disease (CD) trials. We conducted a meta-analysis of phase 2/3 placebo-controlled trials evaluating advanced therapies in moderate-to-severe CD (2010-2021). Deidentified IPD were obtained through Vivli Inc. and Yale University Open Data Access Project. Primary outcomes were clinical response and remission. Pooled placebo rates and 95% confidence intervals (CIs) were estimated using one- and two-stage meta-analytical approaches. Regression analyses identified patient-level factors associated with placebo rates. Using IPD from eight induction (n=1147) and four maintenance (n=524) trials, overall placebo clinical response and remission rates for induction were 27% (95%CI=23-32%) and 10% (95%CI=8-14%) respectively, and 32% (95%CI=23-42%) and 22% (95%CI=14-33%) for maintenance, respectively. Among bio-naïve patients, placebo response and remission rates during induction were 29% (95%CI=24-35%) and 11% (95%CI=8-15%) respectively, and 26% (95% CI=20-33%) and 10% (95% CI=8-14%) for bio-exposed, respectively. During maintenance, bio-naïve response and remission rates were 41% (95%CI=34-48%) and 32% (95%CI=24-40%), respectively, and 29% (95%CI=24-34%) and 16% (95%CI=13-21%) for bio-exposed, respectively. Higher baseline C-reactive protein concentration predicted lower placebo rates, while higher baseline albumin levels and body mass index increased the odds of placebo outcomes. Increased baseline Crohn's Disease Activity Index and 2-item patient-reported outcome scores predicted higher response rates in induction, lower response rates in maintenance, and lower remission rates in induction and maintenance. Patient- and trial-level characteristics influence placebo rates in CD trials. Careful implementation of eligibility criteria, outcome definitions, and patient stratification may reduce placebo rates.

P1013 Placebo rates in Crohn's disease: An individual patient data meta-analysis from multiple randomised controlled trials

Abstract Background Estimating placebo rates and their determinants is essential for designing efficient randomised clinical trials (RCTs) in inflammatory bowel disease. We conducted an individual patient data (IPD) meta-analysis of placebo data from RCTs in Crohn’s disease (CD). Methods MEDLINE, Embase, and CENTRAL were searched from 01/2010 to 01/2020 for contemporary phase 2 and 3 placebo-controlled RCTs of biologics in moderate-to-severe CD. De-identified IPD from eligible trials that were available through the Vivli and Yale University Open Data Access data-sharing platforms were obtained. Primary outcomes were placebo clinical response and remission. Pooled placebo rates and 95% CIs were estimated using a 2-stage meta-analytical approach. Significant patient-level factors (P<0.05) associated with placebo rates were identified using regression analyses. Results Placebo IPD were available from 8 induction (n=1147) and 4 maintenance trials (n=524). Pooled placebo clinical response and remission rates varied based on outcome definition and prior biologic exposure (Figure). In induction trials, overall placebo response and remission rates were 27% (95% CI 23-32%) and 10% (95% CI 8-14%), respectively. Among bio-exposed patients, placebo response and remission rates were 27% (95% CI 16-40%) and 9% (95% CI 6-15%), respectively, compared with 29% (95% CI 24-34%) and 11% (95% CI 8-15%) for bio-naïve patients. Overall placebo response and remission rates in maintenance trials were 32% (95% CI 23%-42%) and 22% (95% CI 14-33%), respectively. Corresponding placebo response and remission rates for bio-exposed patients were 21% (95% CI 8-46%) and 17% (95% CI 11-25%), and 36% (95% CI 28-44%) and 24% (95% CI 15-36%) for bio-naïve patients. Placebo rates were lowest when response was defined as a ≥100-point decrease from baseline in the Crohn's Disease Activity Index (CDAI) score, and when remission was defined using stool frequency (≤1.5) and abdominal pain (≤1) subscores. Higher baseline C-reactive protein concentrations were associated with lower odds of placebo response and remission, while higher baseline albumin levels increased the odds of these outcomes (Table). Increased baseline CDAI and 2-item patient-reported outcome (PRO2) scores predicted higher odds of placebo response in induction trials, yet this reduced the odds of remission in induction trials and of both outcomes in maintenance trials. Prior failure to tumour necrosis factor (TNF) antagonist therapy was more predictive than prior TNF antagonist/biologic exposure for reducing the odds of placebo response and remission. Conclusion Placebo rates and the patient-level factors influencing them vary according to study design, clinical outcome measure and outcome definitions.

A disease model predicting placebo response and remission status of patients with ulcerative colitis using modified Mayo score.

The Mayo Clinical Score is used in clinical trials to describe the clinical status of patients with ulcerative colitis (UC). It comprises four subscores: rectal bleeding (RB), stool frequency (SF), physician's global assessment, and endoscopy (ENDO). According to recent US Food and Drug Administration guidelines (Ulcerative colitis: developing drugs for treatment, Guidance Document, https://www.fda.gov/regulatory-information/s. 2022), clinical response and remission should be based on modified Mayo Score (mMS) relying on RB, SF, and ENDO. Typically, ENDO is performed at the beginning and end of each phase, whereas RB and SF are more frequently available. Item response theory (IRT) models allow the shared information to be used for prediction of all subscores at each observation time; therefore, it leverages information from RB and SF to predict ENDO. A UC disease IRT model was developed based on four etrolizumab phase III studies to describe the longitudinal mMS subscores, placebo response, and remission at the end of induction and maintenance. For each subscore, a bounded integer model was developed. The placebo response was characterized by a mono-exponential function acting on all mMS subscores similarly. The final model reliably predicted longitudinal mMS data. In addition, remission was well-predicted by the model, with only 5% overprediction at the end of induction and 3% underprediction at the end of maintenance. External evaluation of the final model using placebo arms from five different studies indicated adequate performance for both longitudinal mMS subscores and remission status. These results suggest utility of the current disease model for informed decision making in UC clinical development, such as assisting future clinical trial designs and evaluations.

Placebo response in trials with patients with anxiety, obsessive-compulsive and stress disorders across the lifespan: a three-level meta-analysis

QuestionRandomised controlled trials assessing treatments for anxiety, obsessive-compulsive and stress-related disorders often present high placebo response rates in placebo groups. Understanding the placebo response is essential in accurately estimating the...

Placebo Response Rates in Randomized Controlled Trials for Perianal Crohn's Disease: A Systematic Review and Meta-Analysis.

Perianal fistulizing disease is a common complication of Crohn's disease [CD], for which new therapies are urgently needed. To assist the design of clinical trials for novel therapeutics, we conducted a systematic review and meta-analysis of randomised controlled trials [RCTs] to quantify placebo rates and identify factors influencing them in perianal CD [pCD]. We searched MEDLINE, Embase and CENTRAL from inception to June 2021. Eligible studies were placebo-controlled trials of pharmacological interventions for pCD. Placebo fistula response and remission rates for induction and maintenance trials were extracted and pooled using a random-effects model. Mixed-effects meta-regression was used to evaluate the impact of patient and study-level characteristics on point estimates. In 17 RCTs [13 induction, five maintenance] the pooled placebo fistula response and remission rate for induction trials was 25% (95% confidence interval [CI] 17-36%) and 17% [95% CI 11-25%], respectively. For maintenance trials, the pooled placebo fistula response and remission rate was 23% [95% CI 17-32%] and 19% [95% CI 14-25%], respectively. Trials enrolling patients with less disease activity and a higher proportion with ileal predominant disease were associated with significantly higher placebo response rates. Trials originating in Europe [compared to North America], therapies requiring perianal injection and a longer timepoint to measure remission were associated with higher placebo remission rates. Placebo response and remission rates in pCD trials are influenced by patient and disease-related factors, as well as the type of intervention being studied. These contemporary rates will inform trial design for novel therapeutics.

Predictors of Placebo Induction Response and Remission in Ulcerative Colitis

High placebo response rates in clinical trials of ulcerative colitis (UC) have been reported previously. However, data from patient-level analyses are lacking. We assessed factors associated with clinical and endoscopic placebo response among placebo-treated patients in clinical trials of UC. We performed a post hoc analysis of pooled clinical trial data from GEMINI-1, ACT-1, ACT-2, PURSUIT, ULTRA-2, OCTAVE-1, and OCTAVE-2. Predictors were assessed in placebo-treated patients for their association with end of induction (week 6 of 8) clinical response (reduction in total Mayo score of ≥3 and ≥30% from baseline with ≥1 point decrease in rectal bleeding subscore [RBS] or absolute RBS ≤1); clinical remission (total Mayo score ≤2 and no subscore >1); endoscopic healing (Mayo endoscopic subscore ≤1); partial Mayo score of 0; patient-reported outcome 2-item remission (RBS of 0 and stool frequency ≤1), resolution of rectal bleeding, and stool frequency normalization. Predictors on univariate analyses with P < .05 were included in multivariate logistic regression models. Placebo-treated patients with normal serum C-reactive protein and albumin levels were more likely to attain clinical response (71 of 437 [16.3%] vs 49 of 660 [7.4%]; adjusted odds ratio, 2.76; 95% confidence interval, 1.19-5.41; P= .018). Compared with patients with a Mayo endoscopic score of 2, patients with a Mayo endoscopic score of 3 were less likely to attain clinical response (105 of 556 [18.8%] vs 179 of 675 [25.9%]; adjusted odds ratio, 0.33; 95% confidence interval, 0.16-0.68; P= .003). Similar findings were observed for clinical remission and resolution of rectal bleeding. Biomarkers such as normal serum C-reactive protein and albumin and baseline endoscopic severity were found to affect placebo response rates in clinical trials of UC. These findings have implications for clinical trial design in UC.

Placebo Rates in Randomized Controlled Trials of Proctitis Therapy: A Systematic Review and Meta-Analysis Placebo Response in Proctitis.

Treatment options for proctitis are limited. To assist trial design for novel therapeutics, we conducted a systematic review and meta-analysis of proctitis randomized controlled trials [RCTs] to quantify placebo rates and identify factors influencing them. We searched MEDLINE, EMBASE and CENTRAL from inception to June 2021. Placebo-controlled trials of pharmacological interventions for proctitis were eligible. Placebo clinical response and remission rates for induction and maintenance trials were extracted and pooled using a random-effects model. Mixed-effects meta-regression was used to evaluate the impact of patient and study-level characteristics. Twenty RCTs [17 induction and four maintenance phases] were included. The most common intervention was aminosalicylates and most studies investigated topical medications. The pooled placebo clinical response and remission rates for induction trials were 28% (95% confidence interval [CI] 22-35%; n = 17) and 20% [95% CI 12-32%; n = 9], respectively. Pooled placebo endoscopic response and remission rates were 32% [95% CI 26-39%, n = 12] and 18% [95% CI 9-33%, n = 6], respectively. For maintenance trials, the pooled placebo clinical remission rate was 29% [95% CI 16-46%, n = 17]. Trials published after 2005 and trials with a longer duration of follow-up were associated with significantly lower placebo response rates. Nineteen of 20 studies were assessed as having an unclear risk of bias, reflecting the historical nature of trials. Placebo response and remission rates in proctitis trials are influenced by trial phase and the endpoint being assessed. These contemporary rates will inform trial design for novel therapeutics for treatment of proctitis, which is a large unmet need.

Clinical, Endoscopic, and Safety Placebo Rates in Induction and Maintenance Trials of Crohn's Disease: Meta-Analysis of Randomised Controlled Trials.

Precision in estimating placebo rates is important for clinical trial design. To quantify placebo rates across relevant endpoints in Crohn's disease [CD] trials and identify the factors influencing these rates in a contemporary meta-analysis. We searched MEDLINE, EMBASE, and CENTRAL from inception to March 2021. Eligible studies were placebo-controlled trials of pharmacological interventions for CD. Placebo response and remission rates for induction and maintenance trials were extracted and pooled by random-effects to quantify placebo rates across studies. Mixed-effects meta-regression was used to evaluate the effects of study-level characteristics on placebo rates. In 125 studies [91 induction, 46 maintenance], placebo clinical remission and response rates for induction studies were 18% (95% confidence interval [CI] 16, 21%], and 32% [95% CI 29, 35%], respectively, and for maintenance studies were 28% [95% CI 23, 34%] and 30% [95% CI 24, 37%], respectively. Endoscopic remission and response rates in induction studies were 8% [95% CI 4, 18%] and 16% [95% CI 11, 23%], respectively. Trials enrolling patients with prior biologic exposure, longer disease duration, and higher CD activity index scores were associated with lower placebo clinical remission rates. Increased duration of follow-up, more follow-up visits, and a greater proportion of patients with colonic disease distribution were associated with higher clinical placebo rates. Placebo remission and response rates in CD trials vary according to the phase of the trial, endpoint assessed, and induction or maintenance design. These contemporary estimates will help to inform future CD trial design.

Systematic Review and Meta-Analysis: Clinical, Endoscopic, Histological and Safety Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis.

Quantifying placebo rates and the factors influencing them are essential to inform trial design. We provide a contemporary summary of clinical, endoscopic, histological and safety placebo rates in induction and maintenance clinical trials of ulcerative colitis, and identify factors influencing them. MEDLINE, EMBASE and the Cochrane library were searched from April 2014 to April 2020, updating a prior meta-analysis that searched from inception to April 2014. We included placebo-controlled trials of aminosalicylates, corticosteroids, immunosuppressives, small-molecules and biologics in adults with ulcerative colitis. Placebo rates were pooled using random-effects and mixed-effects meta-regression models to assess the associated study-level. In 119 trials [92 induction, 27 maintenance] clinical, endoscopic and histological remission placebo rates for induction trials were 11% (95% confidence interval [CI] 9-13%), 19% [95% CI 15-23%] and 15% [95% CI 11-19%], respectively; for maintenance trials, clinical and endoscopic placebo remission rates were 18% [95% CI 12-25%] and 20% [95% CI 15-25%], respectively. Higher endoscopic subscore and a higher rate of exposure to prior biologic therapy at enrolment were associated with lower clinical and endoscopic placebo remission rates. Absence of central reading was associated with an increase in placebo endoscopic response and remission rates. More follow-up visits and increasing trial duration were associated with higher clinical placebo rates. Placebo rates in ulcerative colitis trials vary according to the endpoint assessed, whether it is for assessment of response or remission, and whether the trial is designed for induction or maintenance. These contemporary rates across different endpoints and drug classes will help to inform trial design.

Placebo Effects in Antidepressant Trials Across Four Decades: A Comparison of Binary and Continuous Outcomes

Background: Previous work suggested placebo response rate in antidepressant trials to be stable since the 1970s. The present analysis aimed to compare placebo response with placebo remission (both binary outcomes) and placebo efficacy (continuous outcome, based on the Hamilton Depression Scale), thereby considering previously suggested (but not assessed) nonlinear time trends and accounting for previously suggested (but not properly adjusted for) small-study effects (SSE). Methods: Random-effects meta-regression was conducted to estimate the effects of study year. Potential nonlinear effects of study year were modeled using restricted cubic splines (RCS). Relative importance of SSE compared to other trial-level covariates (study centers, dosing schedule, study length) was assessed using multimodel averaging. Findings: Multimodel averaging suggested any nonlinear time trends in placebo response (0·07 [-0·05-0·18] 95% CI) and remission (0·00 [-0·01-0·02] 95% CI) to be sufficiently explained by SSE and other trial-level covariates, with between-trial heterogeneity being reduced to I2 =55%/672%, respectively. This suggested stable rates across years, in line with previous work. By contrast, efficacy (continuous) showed an increasing trend from 1979 to 2914 (0·11 [0·02-0·21] 95% CI) with substantial between-trial heterogeneity being unexplained (I2 =85%). Interpretation: The present analysis reports differences in the time trends between binary and continuous placebo outcomes across decades. The findings are discussed regarding their clinical relevance because increasing placebo effects have been suspected of contributing to so-called failed antidepressant trials. Funding Statement: The authors stated: No funding. Declaration of Interests: The author declares no competing interests. Ethics Approval Statement: The authors declared: Not applicable.

Early score fluctuation and placebo response in a study of major depressive disorder

Early score fluctuation in double-blind, placebo-controlled studies may affect the reliability of the baseline measurement and adversely affect the eventual study outcome. We examined the effect of early score fluctuation during a 2-week double-blind placebo lead-in period in a phase II, double-blind, placebo-controlled trial of adjunctive s-adenosyl methionine (MSI-195) in MDD subjects who had had an inadequate response to ongoing antidepressant treatment. The overall study failed to meet its specified endpoints.We examined the score trajectories of all placebo-assigned subjects during the double-blind placebo lead-in period and subsequent 6-week treatment period. Placebo-assigned subjects with ≥20% HamD17 or MADRS score fluctuations (improvement or worsening) during the double-blind placebo lead-in period (prior to randomization) had significantly higher rates of placebo response and remission at week 8 compared to subjects with <20% response. A post-hoc analysis of evaluable subjects taken from the ITT population that excluded subjects with ≥20% early score response yielded higher effect sizes for both the HamD17 and MADRS sub-groups and statistical significance for MSI-195 over placebo in the MADRS sub-group (p = 0.012) with an effect size of 0.404.A reliable baseline measure is an asset for signal detection. These post-hoc findings suggest that study designs that anticipate and attempt to manage early response prior to randomization may yield more meaningful outcome data for trials of MDD and possibly other disorders as well.

P081 HISTOLOGIC HEALING RATES OF MEDICAL THERAPIES FOR ULCERATIVE COLITIS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Histologic remission is a potentially valuable means of assessing disease activity and treatment response in ulcerative colitis (UC). However, the efficacy of existing therapies to achieve this outcome is unclear. We performed a systematic review and meta-analysis of histologic outcomes in UC randomized controlled trials (RCTs) and examined the relationship between histologic and endoscopic outcomes. MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD Register were searched for RCTs of aminosalicylates, corticosteroids, immunosuppresives, biologics and small molecules. Histologic and endoscopic remission and response data were independently extracted and pooled using binomial-normal random or fixed-effects models. Pooled efficacy estimates were calculated as risk ratios (RRs) using the Mantel-Haenszel method. Univariable and multivariable random-effect meta-regression models examined factors associated with histologic remission. Seventy-four studies (68 induction, 7 maintenance) were identified. Topical aminosalicylate enemas (37.2%, 95%CI 29.0-46.3%) and suppositories (44.9%, 95%CI 28.9- 62.3%) had the highest induction of histologic remission rates. Aminosalicylate enemas (RR=4.14, 95%CI 2.35-7.31), aminosalicylate suppositories (RR=3.94, 95%CI 1.26-12.32) and budesonide MMX (RR=1.47, 95%CI 1.08-1.99) had higher histologic remission rates than placebo. Studies of other medications either provided continuous histologic data in distinction to rates of response and remission (approved tumor necrosis factor (TNF) antagonists, antiintegrin therapies, non-conventional biologics) or had insufficient studies for meta-analysis (azathioprine, biologics not approved for UC therapy, small molecules). The pooled histologic remission rate for placebo in induction studies was 10.4% (95%CI 7.1-15.2%). Histologic and endoscopic remission correlated strongly (r=0.66 95%CI 0.50-0.78). In multivariate analysis of placebo-arm data, less severe clinical disease activity (OR=1.85, 95% CI 1.14-2.99, p=0.012) and corticosteroid use (OR=1.28, 95% CI 1.02-1.62, p=0.036) were associated with higher histologic remission rates. Similarly, mild clinical disease activity was associated with higher histologic remission rates (OR=1.19, 95% CI 1.07-1.33, p=0.0020) when active-arm data were analyzed. Histologic remission rates for current UC treatments ranged from 15.0% to 44.9% according to drug class and patient population with the highest rates observed for topical aminosalicylates. Placebo remission rates were low with relatively narrow confidence intervals. These data provide benchmarks to inform future trial design. Histologic remission is a potential treatment target in clinical practice.

Histologic Healing Rates of Medical Therapies for Ulcerative Colitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Histologic remission is a potentially valuable means of assessing disease activity and treatment response in ulcerative colitis (UC). However, the efficacy of existing therapies to achieve this outcome is unclear. We performed a systematic review and meta-analysis of histologic outcomes in UC randomized controlled trials and examined the relationship between histologic and endoscopic outcomes. MEDLINE, EMBASE, CENTRAL, and the Cochrane IBD Register were searched for randomized controlled trials of aminosalicylates, corticosteroids, immunosuppressives, biologics, and small molecules. Histologic and endoscopic remission and response data were independently extracted and pooled using binomial-normal random-effect or fixed-effect models. Pooled efficacy estimates were calculated as risk ratios (RRs) using the Mantel-Haenszel method. Univariable and multivariable random-effect meta-regression models examined factors associated with histologic remission. Seventy-four studies (68 induction and 7 maintenance) were identified. Topical aminosalicylate enemas [37.2%, 95% confidence interval (CI), 29.0-46.3] and suppositories (44.9%, 95% CI, 28.9-62.3) had the highest induction of histologic remission rates. Aminosalicylate enemas (RR = 4.14, 95% CI, 2.35-7.31), aminosalicylate suppositories (RR = 3.94, 95% CI, 1.26-12.32), and budesonide multimatrix (RR = 1.47, 95% CI 1.08-1.99) had higher histologic remission rates than placebo. Data were lacking for biologics and immunosuppressives. The pooled histologic remission rate for placebo in induction studies was 10.4% (95% CI, 7.1-15.2). Histologic and endoscopic remission correlated strongly (r = 0.66; 95% CI, 0.50-0.78). In multivariate analysis of placebo-arm data, less severe clinical disease activity and corticosteroid use were associated with higher histologic remission rates. Similarly, mild clinical disease activity was associated with higher histologic remission rates when active-arm data were analyzed. Histologic remission rates for current UC treatments ranged from 15.0% to 44.9% according to drug class and patient population with the highest rates observed for topical aminosalicylates. Placebo remission rates were low with relatively narrow CIs. These data provide benchmarks to inform future trial design. Histologic remission is a potential treatment target in clinical practice.

Late breaking abstracts

Late breaking abstracts

Systematic review with meta-analysis: endoscopic and histologic placebo rates in induction and maintenance trials of ulcerative colitis.

Regulatory requirements for claims of mucosal healing in ulcerative colitis (UC) will require demonstration of both endoscopic and histologic healing. Quantifying these rates is essential for future drug development. To meta-analyse endoscopic and histologic placebo response and remission rates in UC randomised controlled trials (RCTs) and identify factors influencing these rates. MEDLINE, EMBASE and the Cochrane Library were searched from inception to March 2017 for placebo-controlled trials of pharmacological interventions for UC. Endoscopic and histologic placebo rates were pooled by random effects. Mixed effects univariable and multivariable meta-regression was used to evaluate the influence of patient, intervention and trial-related study-level covariates on these rates. Fifty-six induction (placebo n=4171) and 8 maintenance trials (placebo n=1011) were included. Pooled placebo endoscopic remission and response rates for induction trials were 23% [95 confidence interval (CI) 19-28%] and 35% [95% CI 27-42%] respectively, and 20% [95% CI 16-24%] for maintenance of remission. The pooled histologic placebo remission rate was 14% [95% CI 8-22%] for induction trials. High heterogeneity was observed for all outcomes (I2 56.2%-88.3%). On multivariable meta-regression, central endoscopy reading was associated with significantly lower endoscopic placebo remission rates (16% vs 25%; OR=0.52, [95% CI 0.29-0.92], P=0.03). On univariable meta-regression, higher histologic placebo remission was associated with concomitant corticosteroids (OR=1.17 [95% CI 1.08-1.26], P<0.0001, per 10% increase in corticosteroid use). Placebo endoscopic and histologic rates range from 14% to 35% in UC RCTs but are highly heterogeneous. Outcome standardisation may reduce heterogeneity and is needed in this field.

20 ETROLIZUMAB IMPROVED ENDOSCOPIC SCORE, PATIENT-REPORTED OUTCOMES, AND INFLAMMATORY BIOMARKERS IN PATIENTS WITH MODERATE TO SEVERE UC WHO HAD FAILED TNF ANTAGONIST THERAPY: THE HICKORY OPEN-LABEL INDUCTION (OLI) COHORT

Patients with ulcerative colitis (UC) who have experienced failure of TNF antagonist (aTNF) therapy are a difficult-to-treat population with a notable unmet medical need. Centrally read endoscopy demonstrates reduced placebo remission rates as low as 0%–8% in this population (1,2). HICKORY OLI evaluates etrolizumab in patients intolerant/refractory to aTNFs. Patients received etrolizumab 105 mg every 4 weeks in a 14-week induction period. Endoscopic subscore (ES) and patient-reported rectal bleeding (RB) and stool frequency (SF) were assessed at baseline (BL) and week 14. Assessed outcomes were clinical response: ≥ 3-point and 30% reduction of Mayo Clinic score (MCS) from BL and ≥ 1-point decrease in RB or RB ≤ 1; remission: MCS ≤ 2, with individual subscores ≤ 1 and RB = 0; endoscopic improvement: ES ≤ 1; RB remission: RB = 0; SF remission: SF ≤ 1 with ≥ 1-point reduction from BL. HICKORY OLI enrolled 130 patients with aTNF failure; 45% with failure of > 1 aTNF. BL scores were mean MCS of 9.4 and median fecal calprotectin (FC) of 1778 mg/kg. At week 14, SF remission was achieved in 35.4% of patients, RB remission in 52.3%, clinical response in 50.8%, remission in 12.3%, and ES ≤ 1 in 23.9%. In the 43.9% of patients with ≥ 1-point improvement in ES, there was an association with higher rates of SF and RB remission. Among those with ES = 0, 90% reported SF ≤ 1, and 100% reported RB ≤ 1 (Fig 1). Patients achieving SF remission, RB remission, or ES ≤ 1 demonstrated > 70% geometric mean reduction in FC. In aTNF-failed patients with high disease burden, etrolizumab achieved clinically meaningful response, remission, and endoscopic improvement. Patients who had improved ES achieved higher rates of RB and SF remission and greater reductions in inflammatory biomarkers. Recruitment is ongoing. 1. Vermeire S, et al. Lancet. 2014;384:309–318. 2. Sandborn W, et al. N Engl J Med. 2017;376:1723–1736.

Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis.

Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis.

Systematic review with meta-analysis: placebo rates in induction and maintenance trials of Crohn's disease.

Minimising placebo response is essential for drug development. To conduct a meta-analysis to determine placebo response and remission rates in trials and identify the factors affecting these rates. MEDLINE, EMBASE and CENTRAL were searched from inception to April 2014 for placebo-controlled trials of pharmacological interventions for Crohn's disease. Placebo response and remission rates for induction and maintenance trials were pooled by random-effects and mixed-effects meta-regression models to evaluate effects of study-level characteristics on these rates. In 100 studies containing 67 induction and 40 maintenance phases and 7638 participants, pooled placebo remission and response rates for induction trials were 18% [95% confidence interval (CI) 16-21%] and 28% (95% CI 24-32%), respectively. Corresponding values for maintenance trials were 32% (95% CI 25-39%) and 26% (95% CI 19-35%), respectively. For remission, trials enrolling patients with more severe disease activity, longer disease duration and more study centres were associated with lower placebo rates, whereas more study visits and longer study duration was associated with higher placebo rates. For response, findings were opposite such that trials enrolling patients with less severe disease activity and longer study duration were associated with lower placebo rates. Placebo rates varied by drug class and route of administration, with the highest placebo response rates observed for biologics. Placebo rates vary according to whether trials are designed for induction or maintenance and the factors influencing them differ for the endpoints of remission and response. These findings have important implications for clinical trial design in Crohn's disease.

Placebo response and remission rates in randomised trials of induction and maintenance therapy for Crohn’s disease

Placebo response and remission rates in randomised trials of induction and maintenance therapy for Crohn’s disease

Systematic Review and Meta-analysis: Placebo Rates in Induction and Maintenance Trials of Ulcerative Colitis.

Minimisation of the placebo responses in randomised controlled trials [RCTs] is essential for efficient evaluation of new interventions. Placebo rates have been high in ulcerative colitis [UC] clinical trials, and factors influencing this are poorly understood. We quantify placebo response and remission rates in UC RCTs and identify trial design factors influencing them. MEDLINE, EMBASE, and the Cochrane Library were searched from inception through April 2014 for placebo-controlled trials in adult patients with UC of a biological agent, corticosteroid, immunosuppressant, or aminosalicylate. Data were independently doubly extracted. Quality was assessed using the Cochrane risk of bias tool. In all, 51 trials [48 induction and 10 maintenance phases] were identified. Placebo response and remission rates were pooled according to random-effects models, and mixed-effects meta-regression models were used to evaluate effects of study-level characteristics on these rates. Pooled estimates of placebo remission and response rates for induction trials were 10% (95% confidence interval [CI] 7-13%) and 33% [95% CI 29-37%], respectively. Corresponding values for maintenance trials were 19% [95% CI 11-30%] and 22% [95% CI 17-28%]. Trials enrolling patients with more active disease confirmed by endoscopy [endoscopy subscore ≥ 2] were associated with lower placebo rates. Conversely, placebo rates increased with increasing trial duration and number of study visits. Objective assessment of greater disease activity at trial entry by endoscopy lowered placebo rates, whereas increasing trial duration and more interactions with healthcare providers increased placebo rates. These findings have important implications for design and conduct of clinical trials.