Search

BACKGROUND: Olorinab is a highly selective, peripherally acting, full agonist of cannabinoid receptor 2. This study assessed the efficacy and safety of olorinab to treat abdominal pain in patients with irritable bowel syndrome with diarrhea (IBS-D) and constipation (IBS-C). METHODS: CAPTIVATE was a phase 2b, randomized, double-blind, placebo-controlled, parallel-group trial. Eligible participants aged 18-70 years with IBS-C and IBS-D diagnosed per Rome IV received olorinab 10 mg, 25 mg, or 50 mg three times daily (TID) or placebo TID for 12 weeks. The primary endpoint was the change in patient-reported average abdominal pain score (AAPS) from baseline to Week 12. KEY RESULTS: A total of 273 participants were randomized to receive olorinab 10 mg (n = 67), olorinab 25 mg (n = 67), olorinab 50 mg (n = 69), or placebo (n = 70). Although a treatment response was observed across all groups, the weekly change in average AAPS from baseline to Week 12 was not significantly different between placebo and any olorinab dose. In a prespecified subgroup analysis of participants with a baseline AAPS ≥6.5, olorinab 50 mg (n = 35) significantly improved AAPS compared with placebo (n = 30) (p = 0.014). Adverse event rates were comparable between olorinab and placebo and there were no reported serious adverse events or deaths. CONCLUSION AND INFERENCES: Although olorinab was well-tolerated and improved weekly AAPS, the primary endpoint was not met. However, in participants with moderate-to-severe pain at baseline (AAPS ≥6.5), olorinab 50 mg significantly improved weekly AAPS compared with placebo. CLINICALTRIALS: gov: NCT04043455. ispartof: NEUROGASTROENTEROLOGY AND MOTILITY vol:35 issue:5 ispartof: location:England status: published

Background This randomized, open-label phase 2a study investigated the safety/tolerability, pharmacokinetics, and efficacy of olorinab—a highly selective, peripherally acting, full agonist of the cannabinoid receptor 2—in patients with Crohn’s disease (CD) experiencing abdominal pain. Methods Eligible subjects 18–80 years of age with quiescent to mildly active CD were randomized to receive olorinab 25 or 100 mg three times daily for 8 weeks. The primary objective was to assess safety/tolerability. Results Fourteen subjects received olorinab 25 mg (N = 6) or 100 mg (N = 8). Ten subjects [4 (67%) in the 25-mg group and 6 (75%) in the 100-mg group] reported a total of 34 treatment-emergent adverse events (TEAEs; 32 grade 1/2, not serious events; 2 grade 3, serious, not treatment-related events). No dose reductions or discontinuations due to TEAEs or deaths were reported. Dose-proportional increases in olorinab exposure from 25 to 100 mg were observed, with minimal accumulation at both doses. At week 8, the mean (SD) change from baseline in average abdominal pain score at peak olorinab plasma concentrations was −4.61 (1.77) in the 25-mg group (P = 0.0043) and −4.57 (2.17) in the 100-mg group (P = 0.0036). The change from baseline at week 8 in the mean (SD) number of pain-free days per week was +1.60 (2.61) in the 25-mg group and +2.33 (3.62) in the 100-mg group. No subject required pain medication on study. Conclusions Patients with quiescent to mildly active CD receiving olorinab experienced mild-to-moderate adverse events and an improvement in abdominal pain scores in this study.

Objective This multicenter, randomized, controlled, open-label trial examined weight-related quality of life, control over eating behaviour and sexual function after 26 weeks of treatment with either 32 mg naltrexone sustained release (SR)/360 mg bupropion SR plus a comprehensive lifestyle intervention program (NB + CLI, N = 153) or usual care (UC, N = 89), which included minimal lifestyle intervention. Methods Impact of Weight on Quality of Life-Lite, Binge Eating Scale and Arizona Sexual Experiences Scale were assessed at baseline (BL) and weeks 16 and 26. Results NB + CLI and UC participants lost 9.46 and 0.94% respectively of initial body weight at week 26 (P

Objective This study assessed the effects of 32 mg naltrexone sustained release (SR)/360 mg bupropion SR (NB) on body weight in adults with obesity, with comprehensive lifestyle intervention (CLI), for 78 weeks. Methods In this phase 3b, randomized, open-label, controlled study, subjects received NB + CLI or usual care (standard diet/exercise advice) for 26 weeks. NB subjects not achieving 5% weight loss at week 16 were discontinued, as indicated by product labeling. After week 26, usual care subjects began NB + CLI. Assessments continued through week 78. The primary end point was percent change in weight from baseline to week 26 in the per protocol population. Other end points included percentage of subjects achieving ≥5%, ≥10%, and ≥15% weight loss, percent change in weight at week 78, and adverse events (AEs) necessitating study medication discontinuation. Results NB + CLI subjects lost significantly more weight than usual care subjects at week 26 (8.52% difference; P < 0.0001). Weight loss persisted through 78 weeks. In total, 20.7% of subjects discontinued medication for AEs, including 7.0% for nausea. Conclusions Treatment with NB, used as indicated by prescribing information and with CLI, significantly improved weight loss over usual care alone. NB-facilitated weight loss was sustained for 78 weeks and was deemed safe and well tolerated.

Background Etrasimod is a selective, sphingosine 1-phosphate receptor modulator in development for chronic immune-mediated inflammatory disorders. We evaluated etrasimod pharmacokinetics (PK) and its pharmacodynamic (PD) effect (lymphocyte count) in Japanese and Caucasian healthy male subjects. Methods This phase 1 study comprised 12 men (10 etrasimod; 2 placebo) in each of 4 groups (Japanese, 1 and 2 mg; Caucasian, 1 and 2 mg). Etrasimod or matching placebo was administered once daily (QD) from Days 1 to 7, followed by a 7-day washout and a single dose on Day 15. Blood was intensively sampled on Days 1 and 7 for plasma PK and collected each morning on Days 1 to 15 to measure lymphocyte counts and calculate lymphocyte PD parameters, including Rmin, Rmax, and AUECNet. Results Etrasimod peak (Cmax) and total (AUC0-τ) plasma exposure values in Japanese and Caucasian subjects were dose-dependent and showed low-to-moderate inter-subject variability for each dose. Following single and multiple doses, geometric least squares (LS) mean etrasimod exposure values were slightly-to-moderately higher in Japanese subjects compared with Caucasian subjects; however, corresponding dose-body weight normalised etrasimod exposure values were similar indicating the exposure differences appear mainly attributable to bodyweight differences rather than ethnicity. Dose-dependent decreases in median lymphocyte counts were observed in both ethnicities from Days 2 to 8 and increased back to near baseline levels during the washout period. As expected, only LS mean Rmin and AUECNet values were dose-dependent in both ethnicities (table), with none of the evaluated lymphocyte PD parameters being statistically different between Japanese and Caucasian male subjects. Conclusion These results demonstrate the lack of clinically meaningful PK or PD (lymphocyte response) ethnic differences between Japanese and Caucasian healthy male subjects and support the potential inclusion of Japanese patients with moderately to severely active ulcerative colitis in global phase 3 clinical trials evaluating an etrasimod 2 mg QD dosing regimen.

Objective This study assessed the effects of 32 mg naltrexone sustained release (SR)/360 mg bupropion SR (NB) on body weight in adults with obesity, with comprehensive lifestyle intervention (CLI), for 78 weeks. Methods In this phase 3b, randomized, open‐label, controlled study, subjects received NB + CLI or usual care (standard diet/exercise advice) for 26 weeks. NB subjects not achieving 5% weight loss at week 16 were discontinued, as indicated by product labeling. After week 26, usual care subjects began NB + CLI. Assessments continued through week 78. The primary end point was percent change in weight from baseline to week 26 in the per protocol population. Other end points included percentage of subjects achieving ≥5%, ≥10%, and ≥15% weight loss, percent change in weight at week 78, and adverse events (AEs) necessitating study medication discontinuation. Results NB + CLI subjects lost significantly more weight than usual care subjects at week 26 (8.52% difference; P < 0.0001). Weight loss persisted through 78 weeks. In total, 20.7% of subjects discontinued medication for AEs, including 7.0% for nausea. Conclusions Treatment with NB, used as indicated by prescribing information and with CLI, significantly improved weight loss over usual care alone. NB‐facilitated weight loss was sustained for 78 weeks and was deemed safe and well tolerated.

Study design Meta-analysis of 4 prospective randomized controlled Food and Drug Administration (FDA) Investigational Device Exemption (IDE) clinical trials. Objective To maximize the information available from 4 IDE studies by analyzing the combined outcomes of cervical arthroplasty versus fusion at 24-month follow-up. Summary of background data To date, 4 randomized clinical trials have been completed in the United States under FDA IDE protocols to study cervical arthroplasty. Each trial reported arthroplasty to be at least as successful as fusion controls based on noninferiority trial designs. However, sample sizes in any given trial may not be sufficient to demonstrate superiority of treatment effect. Meta-analysis enables pooling of results from comparable trials, which may lead to more precise and statistically significant estimates of treatment effect. Methods Four cervical arthroplasty randomized clinical trials with comparable enrollment criteria and outcome measures were conducted independently by 3 separate sponsors to study the following devices: Bryan, Prestige, ProDisc-C, and PCM cervical disc replacements. A total of 1608 patients were treated across 98 investigative sites. Data were available for 1352 treated patients, of which 1226 were evaluable at 24 months. Assessments included clinical success definitions based on neck disability index, maintenance or improvement of neurological status, subsequent surgery or intervention at the index level (survivorship), and a composite score comprising these as well as serious device-related adverse events. Trial endpoint comparisons were made at 24 months postoperatively. For each endpoint, a random-effects meta-analysis was performed to compare the success rates of cervical arthroplasty with anterior cervical discectomy and fusion (ACDF). Also, supportive frequentist and bayesian analyses were performed. Results The pooled primary overall success results indicated a statistically significant treatment effect favoring arthroplasty compared with ACDF. Overall success was achieved by 77.6% of the arthroplasty patients and by 70.8% of the ACDF patients (pooled odds ratio [OR]: 0.699, 95% confidence interval [CI]: 0.539-0.908, P = 0.007). The results of the individual subcomponent meta-analyses, all of which favored arthroplasty, were neck disability index success (OR: 0.786, 95% CI: 0.589-1.050, P = 0.103), neurological status (OR: 0.552, 95% CI: 0.364-0.835, P = 0.005), and survivorship (OR: 0.510, 95% CI: 0.275-0.946, P = 0.033). Only the survivorship endpoint suggested low heterogeneity. Conclusion These findings suggest that cervical arthroplasty is superior to ACDF in overall success, neurological success, and survivorship outcomes at 24 months postoperatively.

This phase II, multicenter, single-arm, two-stage study in platinum-resistant, advanced epithelial ovarian or primary peritoneal cancer evaluated the efficacy, safety, and tolerability of weekly single-agent volociximab. Pharmacokinetic/pharmacodynamic (PK/PD) studies were also performed.Sixteen patients were enrolled in Stage 1. Volociximab was administered at 15mg/kg IV qwk until progression of disease or drug intolerability. Tumor response was assessed every 8weeks. Serum samples for PK or whole blood for the evaluation of circulating tumor cells, endothelial cells, and endothelial progenitor cells were obtained on Days 1, 8, 15, 29, and 50. Ascites from one patient was collected for volociximab concentration analysis. Archived tumor tissue was analyzed by immunohistochemistry (IHC) for α5 integrin expression.Safety data are available on all 16 patients; 14 were evaluable for efficacy. One patient had stable disease at 8weeks. The remaining 13 progressed on treatment. Twelve patients (75%) experienced study-related adverse events (AEs); the most common (≥20%) were headache and fatigue. Three patients experienced possible study-related serious AEs (SAEs): reversible posterior leukoencephalopathy syndrome, pulmonary embolism, and hyponatremia. Peak serum concentrations of volociximab increased 2-3 fold from Day 1 to Day 50. Clinically relevant trough levels were achieved (150μg/mL). IHC analysis of archived tumor sections showed low-to-moderate expression of α5 integrin on all ovarian cancer tissue evaluated.Despite insufficient clinical activity in this refractory patient population to continue the study, weekly volociximab was well tolerated, and the gained understanding of the mechanism of action of volociximab will inform future development efforts.

Objective To assess the safety of rituximab in combination with a tumor necrosis factor (TNF) inhibitor and methotrexate (MTX) in patients with rheumatoid arthritis (RA). Methods Adult patients with active RA (≥5 swollen and ≥5 tender joints) receiving a stable dose of MTX (10–25 mg/week) and stable dose of TNF inhibitor (etanercept or adalimumab) for ≥12 weeks were randomized 2:1 to receive one course of rituximab or placebo, given intravenously at a dose of 2 × 500 mg. The primary end point was the proportion of patients developing ≥1 serious infection through week 24. Results Fifty-one patients were treated with either rituximab or placebo in combination with background MTX and a TNF inhibitor. Baseline characteristics were generally balanced between groups, except for corticosteroid usage (36% in the rituximab arm versus 17% in the placebo arm). A serious infection (pneumonia) was observed in 1 patient (3%) in the rituximab group after 14.4 patient-years of exposure (6.95 events per 100 patient-years, 95% confidence interval 0.98–49.35), compared with none in the placebo group at week 24. Infections were reported in 18 patients (55%) and 11 patients (61%) in the rituximab and placebo groups, respectively. Grade 3 infections were reported in 3 patients (9%) receiving rituximab and in none of the patients receiving placebo. No grade 4 infections were observed, nor were there any opportunistic, fungal, or tuberculosis infections. Serious adverse events (SAEs) were reported in 2 rituximab-treated patients (pneumonia and coronary artery occlusion), whereas there were no SAEs reported in placebo-treated patients. At week 24, the percentage of patients achieving an American College of Rheumatology 20% (ACR20) improvement response was 30% in the rituximab group compared with 17% in the placebo group, and ACR50 responses were achieved by 12% and 6% of patients, respectively. Conclusion The preliminary safety profile of rituximab in combination with a TNF inhibitor and MTX was consistent with the safety profile of rituximab in combination with MTX in other RA trials without a TNF inhibitor, with no new safety signals observed. SAEs were numerically more frequent in the rituximab group, and there was no clear evidence of an efficacy advantage in patients receiving rituximab in combination with a TNF inhibitor and MTX.

A modified large-sample (MLS) approach and a generalized confidence interval (GCI) approach are proposed for constructing confidence intervals for intraclass correlation coefficients. Two particular intraclass correlation coefficients are considered in a reliability study. Both subjects and raters are assumed to be random effects in a balanced two-factor design, which includes subject-by-rater interaction. Computer simulation is used to compare the coverage probabilities of the proposed MLS approach (GiTTCH) and GCI approaches with the Leiva and Graybill [1986. Confidence intervals for variance components in the balanced two-way model with interaction. Comm. Statist. Simulation Comput. 15, 301–322] method. The competing approaches are illustrated with data from a gauge repeatability and reproducibility study. The GiTTCH method maintains at least the stated confidence level for interrater reliability. For intrarater reliability, the coverage is accurate in several circumstances but can be liberal in some circumstances. The GCI approach provides reasonable coverage for lower confidence bounds on interrater reliability, but its corresponding upper bounds are too liberal. Regarding intrarater reliability, the GCI approach is not recommended because the lower bound coverage is liberal. Comparing the overall performance of the three methods across a wide array of scenarios, the proposed modified large-sample approach (GiTTCH) provides the most accurate coverage for both interrater and intrarater reliability.

Study design Prospective, multicenter, randomized clinical trial. Objective To evaluate the long-term safety and effectiveness of the PCM Cervical Disc compared with anterior cervical discectomy and fusion (ACDF) in treatment of patients with symptomatic single-level degenerative spondylosis between C3-C4 and C7-T1 with or without prior cervical fusion. Summary of background data The 2-year results of the PCM Cervical Disc trial have been reported previously. The current study reports the long-term results of the same trial. Methods Patients with single-level cervical spondylosis and radiculopathy with or without myelopathy unresponsive to nonoperative treatment were enrolled. The per protocol patient sample at 5 years included 293 patients (163 PCM, 130 ACDF). Adverse events and secondary surgical procedures are reported on the cohorts through current follow-up, which include 110 patients (68 PCM, 42 ACDF) at 7 years. Results At 5 years postoperative, all patient-reported outcomes-neck and arm pain visual analogue scale score, neck disability index, and general health (36-Item Short Form Health Survey physical and mental component scores: physical component summary, mental component summary)-were significantly improved from baselines in both groups, and mean scores were significantly better in the PCM group for neck disability index (P=0.001), neck pain (P=0.002), general health (Pphysical component summary=0.014; Pmental component summary=0.004), and patient satisfaction (P=0.005). PCM patients trended toward fewer 2- to 7-year device-related serious adverse events (1/214, 0.5% PCM; 2/190, 1.1% ACDF) and secondary surgical procedures (7/211, 3.3% PCM; 14/290, 7.6% ACDF). Adjacent-level degeneration was radiographically more frequent after ACDF (33.1% PCM, 50.9% ACDF; P=0.006) and was the primary indication for the increase in late-term secondary surgical procedures after ACDF. Conclusion The long-term results show good clinical outcomes after ACDF and PCM arthroplasty. PCM patients showed greater improvement in neck disability index and neck pain scores with a lower rate of radiographical adjacent-level degeneration and a trend toward fewer secondary surgical procedures. These data support PCM arthroplasty to be a viable and sustainable alternative to ACDF. Level of evidence 1.

Study design Prospective, multicenter, randomized Food and Drug Administration approved investigational device exemption clinical trial. Objective To evaluate the safety and effectiveness of the PCM Cervical Disc compared with anterior cervical discectomy and fusion (ACDF) in the treatment of patients with degenerative spondylosis and neurological symptoms at 1 level between C3-C4 and C7-T1. Summary of background data Cervical disc arthroplasty in the treatment of symptomatic cervical spondylosis has been studied in other series. The PCM Cervical Disc is a nonconstrained motion-sparing alternative to ACDF. Methods Patients 18 to 65 years of age with single-level symptomatic cervical spondylosis with radiculopathy and/or myelopathy unresponsive to nonoperative treatment were enrolled, including patients with prior nonadjacent or adjacent single-level fusions. The per-protocol patient sample at 2 years included 342 patients (189 PCM, 153 ACDF). Longitudinal outcomes were comparatively evaluated. Results At 2 years postoperatively, clinical measures-neck and arm pain visual analogue scale, Neck Disability Index (NDI), SF-36, and neurological status-were significantly improved from preoperative baselines in both groups. Mean NDI score at 2 years was significantly lower in PCM group (P = 0.029). There were no statistical differences between groups in rates of surgery-related serious adverse events (5.6% PCM, 7.4% ACDF) or secondary surgical procedures (5.2% PCM, 5.4% ACDF). Patients with PCM reported lower dysphagia scores (8.8/100 vs. 12.1/100; P = 0.045) and higher patient satisfaction (82.8/100 vs. 81.4/100). Overall success, a composite endpoint including minimum 20% NDI improvement, no major complications, no neurological worsening, no secondary surgical procedures, and meeting radiographical criteria of motion for PCM and fusion for ACDF, was significantly greater in the PCM group (75.1% vs. 64.9%; P = 0.020). Conclusion The treatment of symptomatic single-level cervical spondylosis with PCM achieves clinical outcomes that are at least equivalent to ACDF while maintaining motion. At 2 years, patients with PCM had lower NDI scores, statistically lower rate of prolonged dysphagia, greater patient satisfaction, and superior overall success.

Oncology clinical trials are often complex leading to years of research and generation of vast amounts of data. Statistical graphics play an invaluable role in transforming these multifaceted data into crisp and simplified visuals that assist researchers to quickly and accurately study the results, detect data trends and patterns, and suggest hypotheses. In other words, “Excellence in statistical graphics consists of complex ideas communicated with clarity, precision, and efficiency.” The focus of this chapter is to provide a sampling of useful statistical graphics routinely used in clinical oncology research and their utility in communicating information clearly and more efficiently than solely reviewing tables of numerical output. The graphics presented are commonly used during trial design planning, interim analyses, and final analyses of clinical efficacy data.