Futility and toxicity monitoring without halting for interim analyses.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13579-e13579
Author(s):  
Diana L Urbauer ◽  
Shannon Neville Westin ◽  
Ying Yuan
Keyword(s):  
Interim Analysis ◽  
Rate Of Change ◽  
Early Termination ◽  
Operating Characteristics ◽  
Expected Number ◽  
Toxicity Monitoring ◽  
Maximum Sample Size ◽  
Number Of Patients ◽  
Accrual Rate ◽  
Assessment Window

e13579 Background: Many trial designs with futility or toxicity monitoring require that accrual halt to wait for currently enrolled patients to complete their assessment window. However, logistics often prevent this. In these cases, the performance of those designs might be compromised. This study examines the performance of 2 popular designs when enrollment is not halted at interim. Methods: Simulations were run to examine the effect of continuous enrollment on the operating characteristics (OCs) of a Simon’s 2-stage design for futility monitoring and a design using Bayesian posterior probabilities for toxicity monitoring. Both sets of 10,000 simulations examined the OCs when accrual rate was 0.5, 1.5, 3 and 5 patients/month with an assessment window of 30, 60 and 180 days. Results: The first scenario examined the OCs of a Simon design with 12 patients in the first stage and 21 at the end of the second stage. Regardless of accrual rate, the expected number of patients (EN0) increased and probability of early termination (PET0) decreased under the null hypothesis. Rate of change increased as assessment window increased. EN0 was 16 and PET0 was 54% when halting enrollment between stages. With continuous enrollment, EN0 ranged from 16-19, 17-21, and 18-21 patients for the 30-, 90- and 180-day assessment windows. PET0 ranged from 54%-50% with a 30-day assessment window. It halved to 24% with 3 patients/month enrolled and a 90-day window. PET0 was essentially 0 with a 180-day window and an enrollment of 3 patients/month. OCs for toxicity monitoring were examined for the early stopping rule Pr(toxicity rate > 0.3 | data) > 0.85 with toxicity rate ̃ beta(1, 1) with a maximum sample size of 20 and cohort size of 5. Expected number of patients (EN) increased and probability of early termination (PET) decreased as accrual rate increased, with rate of change increasing as assessment window increased. When the true probability of toxicity was 50% and enrollment halted between cohorts, EN was 10 patients and PET was 78%. EN was 17 and PET 54% with an assessment window of 30 days and 5 patients were enrolled per month. With a 90-day assessment window and 3 patients/month enrolled, EN was 16 and PET 59%. EN was 20 and PET was 12% with a 180-day assessment window and 3 patients were enrolled per month. Similar results were noted for cohorts of size 10 and a maximum number of 40 patients. Conclusions: The performance of designs that require halting enrollment while waiting for results of an interim analysis can be compromised by continuous accrual when assessment windows are lengthy and the accrual is fast. In these circumstances, consideration should be given to designs, such as Bayesian multiple imputation for delayed outcomes (Cai et al Stat Med 2014) and TOP2 (Lin et al JNCI 2019), that do not require accrual halt to make real-time interim analysis in the presence of pending patients, which protects patients from excessive toxicity or a futile intervention.

scholarly journals Complications of cervical spine manipulation therapy: 5-year retrospective study in a single-group practice

2002 ◽  
Vol 13 (6) ◽  
pp. 1-8 ◽  
Author(s):  
David G. Malone ◽  
Nevan G. Baldwin ◽  
Frank J. Tomecek ◽  
Christopher M. Boxell ◽  
Steven E. Gaede ◽  
...  
Keyword(s):  
Cervical Spine ◽  
Disc Herniation ◽  
Spinal Manipulation ◽  
Cervical Disc ◽  
Published Data ◽  
Complication Rates ◽  
Single Group ◽  
Expected Number ◽  
Manipulation Therapy ◽  
Number Of Patients

Object The authors report a series of 22 patients in whom major complications developed after cervical spinal manipulation therapy (CSMT). A second objective was to estimate the regional incidence of these complications and to compare it with the very low incidences reported in the literature. Methods During a 5-year period, practioners at a single group neurosurgical practice in Tulsa, Oklahoma, treated 22 patients, who were markedly worse during, or immediately after, CSMT. The details of these cases are reported. The 1995 US Government National Census was used to define the regional referral population for Tulsa. The published data regarding the incidence of serious CSMT-related complications and the rate of CSMTs undertaken nationally were used to estimate the expected number of CSMT-related complications in the authors' region. The number (22 cases) reported in this series was used to estimate the actual regional incidence. Complications in the series included radiculopathy (21 cases), myelopathy (11 cases), Brown–Séquard syndrome (two cases), and vertebral artery (VA) occlusion (one case). Twenty-one patients underwent surgery. Poor outcomes were observed in three, outcome was unchanged in one, and 17 improved. The number of patients in this series exceeded the expected number for the region. Conclusions Cervical spinal manipulation therapy may worsen preexisting cervical disc herniation or cause disc herniation resulting in radiculopathy, myelopathy, or VA compression. In cases of cervical spondylosis, CSMT may also worsen preexisting myelopathy or radiculopathy. Manipulation of the cervical spine may also be associated with higher complication rates than previously reported.

scholarly journals Community treatment orders – principles and attitudes

2013 ◽  
Vol 37 (2) ◽  
pp. 58-59 ◽  
Author(s):  
Vimal Kumar Sharma
Keyword(s):  
Community Treatment ◽  
Successful Implementation ◽  
Care Providers ◽  
Community Treatment Orders ◽  
Expected Number ◽  
The Past ◽  
Number Of Patients ◽  
Patient Groups ◽  
Treatment Order ◽  
Community Treatment Order

SummaryThe community treatment order (CTO) was implemented in 2008 as part of the 2007 amendments to the Mental Health Act 1983. Initially, health professionals and patient groups were sceptical about the successful implementation of CTOs. However, as more than the expected number of patients has been subjected to CTOs in the past 3 years in England and Wales, the professionals' views are shifting in favour of CTOs. More needs to be done to improve the approach and attitude of care providers so that CTOs are used in the most appropriate and effective way for the patients.

Quantitative Assessment of Fatty Liver using Ultrasound with Normalized Local Variance Technique

2020 ◽  
Author(s):  
Jae Seok Bae ◽  
Dong Ho Lee ◽  
Jae Young Lee ◽  
Haeryoung Kim ◽  
Su Jong Yu ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Diagnostic Performance ◽  
Receiver Operating Characteristics ◽  
Operating Characteristics ◽  
Ultrasound Technique ◽  
Diffuse Liver Disease ◽  
Local Variance ◽  
Number Of Patients ◽  
History Of ◽  
Receiver Operating

Abstract Purpose To assess the diagnostic performance of the normalized local variance (NLV) ultrasound technique in the detection of the fatty liver using histopathology as a reference standard. Materials and Methods We prospectively enrolled 194 consecutive patients with clinical suspicion of diffuse liver disease or history of liver transplantation. Conventional grayscale ultrasound and NLV examinations were performed and immediately followed by liver biopsies. The degrees of fatty liver, necroinflammatory activity, and fibrosis stage were evaluated by histopathological assessment. The diagnostic performance of the NLV values in detecting each grade of fatty liver was determined using receiver operating characteristics analyses, and multivariate linear regression analyses were performed to identify variables significantly associated with the NLV values. Results The number of patients in each degree of fatty liver and hepatic fibrosis was 118/37/26/13 and 81/68/24/6/14 for none/mild/moderate/severe steatosis and F0 / F1/F2 / F3/F4 fibrosis on histopathological examinations, respectively. The area under the receiver operating characteristics curve and optimal cut-off NLV value for detecting fatty liver of varying degrees were 0.911 and 1.095 for ≥ S1, 0.974 and 1.055 for ≥ S2, and 0.954 and 1.025 for ≥ S3, respectively. Multivariate analyses revealed that not fibrosis or inflammation but rather the degree of steatosis was associated with the NLV value. Conclusion The NLV value demonstrated excellent diagnostic performance for detecting varying degrees of fatty liver, and the degree of steatosis on histopathological examinations was the only significant factor affecting the NLV value.

scholarly journals Colistin versus meropenem in the empirical treatment of ventilator-associated pneumonia (Magic Bullet study): an investigator-driven, open-label, randomized, noninferiority controlled trial

Critical Care ◽  
2019 ◽  
Vol 23 (1) ◽  
Author(s):  
José M. Cisneros ◽  
◽  
Clara María Rosso-Fernández ◽  
Cristina Roca-Oporto ◽  
Gennaro De Pascale ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Empirical Treatment ◽  
Early Termination ◽  
Magic Bullet ◽  
Ventilator Associated Pneumonia ◽  
Efficacy And Safety ◽  
Serious Adverse Events ◽  
Carbapenem Resistant ◽  
Number Of Patients ◽  
Significant Difference

Abstract Background Colistin is recommended in the empirical treatment of ventilator-associated pneumonia (VAP) with a high prevalence of carbapenem-resistant gram-negative bacilli (CR-GNB). However, the efficacy and safety of colistin are not well defined. Methods A multicenter prospective randomized trial conducted in 32 European centers compared the efficacy and safety of colistin (4.5 million unit loading dose followed by a maintenance dose of 3 million units every 8 h) versus meropenem (2 g every 8 h), both in combination with levofloxacin (500 mg every 12 h) for 7–14 days in patients with late VAP. Between May 2012 and October 2015, 232 patients were randomly assigned to the 2 treatment groups. The primary endpoint was mortality at 28 days after randomization in the microbiologically modified intention-to-treat (mMITT) population. Secondary outcomes included clinical and microbiological cure, renal function at the end of the treatment, and serious adverse events. The study was interrupted after the interim analysis due to excessive nephrotoxicity in the colistin group; therefore, the sample size was not achieved. Results A total of 157 (67.7%) patients were included in the mMITT population, 36 of whom (22.9%) had VAP caused by CR-GNB. In the mMITT population, no significant difference in mortality between the colistin group (19/82, 23.2%) and the meropenem group (19/75, 25.3%) was observed, with a risk difference of − 2.16 (− 15.59 to 11.26, p = 0.377); the noninferiority of colistin was not demonstrated due to early termination and limited number of patients infected by carbapenem-resistant pathogens. Colistin plus levofloxacin increased the incidence of renal failure (40/120, 33.3%, versus 21/112, 18.8%; p = 0.012) and renal replacement therapy (11/120, 9.1%, versus 2/112, 1.8%; p = 0.015). Conclusions This study did not demonstrate the noninferiority of colistin compared with meropenem, both combined with levofloxacin, in terms of efficacy in the empirical treatment of late VAP but demonstrated the greater nephrotoxicity of colistin. These findings do not support the empirical use of colistin for the treatment of late VAP due to early termination. Trial registration ClinicalTrials.gov, NCT01292031. Registered 9 February 2011.

Bendamustine Versus Chlorambucil in Treatment-Naive B-CLL Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4817-4817 ◽  
Author(s):  
Wolfgang Ulrich Knauf ◽  
Toshko Lissitchkov ◽  
Raoul Herbrecht ◽  
Javier Loscertales ◽  
Ali Aldaoud ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Remission Rate ◽  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
Safety Analysis ◽  
Phase Iii ◽  
Cross Resistance ◽  
Free Survival ◽  
Number Of Patients ◽  
Treatment Naïve

Abstract Introduction: Bendamustine (BEN) provides effective treatment of hematologic as well as of non-hematologic malignancies. It is characterized by an unique activity profile which differs from common nitrogen mustard drugs. In particular, it causes only partial cross resistance to other alkylating agents, anthracyclines and anti-metabolites, respectively. BEN is used in patients with chemo naïve, relapsed or refractory chronic lymphocytic leukemia (CLL), however, no head-to-head study has been performed so far. Therefore, a multicenter, international phase III study was initiated to compare the activity of BEN against chlorambucil in treatment-naive B-CLL patients with Binet stage B/C. Patients and Methods: Patients are randomized to either Arm A (BEN 100 mg/m2, d 1+2) or to Arm B (chlorambucil 0,8mg/kg Broca’s weight, d 1+15) to receive a maximum of 6 treatment cycles. Primary objectives are overall remission rate and progression-free survival. The anticipated effects are an overall remission rate of 60% vs. 30% and a median progression free survival of 20 vs.14 months. Secondary objectives are additional efficacy parameters, safety, and quality of life. The study design is adaptive with four interim analyses to adjust the final number of patients, plus one safety analysis. A maximum of 350 patients is planned. Toxicities regarding hemoglobin, platelets and neutrophils are graded according to the NCIWG for CLL, while leukocyte and lymphocyte counts are graded according to CTC as in many other CLL trials. Results and Summary: To assess safety, twenty patients in each treatment arm with at least one completed treatment cycle have been evaluated. The results have been reviewed by an independent data monitoring committee (IDMC). It was concluded that the dosages selected for both treatment arms are safe and that the study is to be continued. Furthermore, another safety analysis was performed with respect to the rate of major infections in the same patient cohort after having completed study treatment. While the infection rate has been reported to be 29% in patients treated with fludarabine as published by Rai et al., in our study two BEN-patients (10%) experienced major infections whereas none occurred in the chlorambucil arm. One BEN-patient developed fever CTC grade 3 without neutropenia. Another patient experienced pneumonia CTC grade 2 requiring hospitalization and intravenous antibiotic treatment. In the BEN-arm, 87% of the scheduled dose was applied whereas 89% was given in the chlorambucil arm. Patients treated with BEN remained longer on study as compared to the chlorambucil patients. The toxicity rate, both hematologic and non-hematologic, was in favour for chlorambucil. In total, three patients were withdrawn from study due to toxicity: one patient in each treatment arm due to infection and one BEN-patient due to an allergic reaction. Meanwhile, the first planned interim analysis on remission rate was done. 43 patients in each treatment arm were evaluated. The IDMC recommended to continue the study. A second interim analysis will be performed after 160 patients will have completed the first tumor evaluation to adjust the number of patients finally required.

Efficacy of Iron Chelation in Reducing Cardiac Iron as Assessed by MRI T2* in Patients with Thalassemia Major

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3887-3887
Author(s):  
Vasilios Antonios Berdoukas ◽  
Giorgos Chouliaras ◽  
Panagiotis Moraitis ◽  
Kirikos Zannikos ◽  
Eleni Berdoussi ◽  
...  
Keyword(s):  
Linear Regression Analysis ◽  
Thalassemia Major ◽  
Rate Of Change ◽  
The Other ◽  
Total Period ◽  
Cardiac Iron ◽  
Cardiac Siderosis ◽  
Mri Studies ◽  
Number Of Patients ◽  
Time Varying Covariates

Abstract 241 thalassemia major patients have had repeated evaluation of cardiac iron assessed by Magnetic Resonance Imaging (MRI) over a median interval of 15 months (range 2.6–72.6). We compared changes in T2* between MRI studies with desferrioxamine (DFO) – (number of patients (n)=31, total MRIs (nMRI)=116), deferiprone (DFP) − (n=41 nMRI=94) and combination of DFO and DFP (Comb) − (n=143 nMRI=347) using repeated measurement analysis with correlated error terms and time varying covariates. Patients were divided into four groups according to their baseline cardiac T2* (Heavy load £ 8 ms, moderate load 8–14, mild 314–20 and normal 320). Table 1 shows the overall assessment excluding patients on DFX. These were not included in that assessment as the total period of exposure was statistically significantly less than that of the other regimes. Analysis was therefore performed using student T test to assess the rate of change between the first and second MRI in the T2* values in patients with comparable cardiac siderosis according to each chelation regime adjusted for overall time of exposure (Table 2). With linear regression analysis (Table3) we compared the effect of DFO to the other three regimes in the annual rate of increasing cardiac T2*. The results have been adjusted for baseline T2* and time of exposure to therapy. Both DFP and Comb regimes are superior to DFO in reducing cardiac siderosis. This indicates that over one year DFP and Comb regimes will have a greater increase in T2* than that achieved by DFO. In addition, Comb seems to be superior to DFX as it would increase the T2* by 2ms/year above that which can be achieved by DFX (p=0.007). DFP achieves 1.7ms/year above the annual improvement with DFX but the difference is not statistically significant. The estimated difference in annual improvement of T2* between Comb and DFP is 0.33ms/year (p=0.07) These data confirm that which is seen in clinical practice according to the chelation regimes used. It is clear that the combination of DFO and DFP is the most rapid regime for reducing cardiac iron and seems to be effective at all levels of cardiac siderosis. The ability to assess tissue iron in the heart is extremely clinically valuable and allows preemptive intervention in order to reduce cardiac morbidity and mortality by the selection of the most appropriate chelation therapy according to the MRI findings. Table1 Annual estimated mean change in T2* according to severity of cardiac siderosis Regime Heavy Moderate Mild ΔT2* p ΔT2* p ΔT2* p DFO 0.61 n.s 1.06 n.s. −1.5 n.s. DFP 0.55 <0.001 2.8 <0.001 3.4 <0.001 Comb 1.4 <0.001 3.5 <0.001 2.6 <0.001 Table 2 Annual estimated mean change in T2* according to severity of cardiac siderosis Regime Heavy Moderate Mild ΔT2* P ΔT2* p ΔT2* p *tm= mean time (in months) between MRI studies DFO n= 73 tm*= 23 0.73 0.05 1.07 0.09 0.9 0.4 DFP n= 53 tm=18.5 1.95 0.14 3.2 0.0045 3.9 0.06 Comb n= 152 tm=21.2 1.98 <0.001 4.4 <0.001 5.7 0.0025 DFX n=96 tm=14.9 −0.51 0.41 −0.67 0.4 4.2 0.23 Table 3 Mean estimated difference in T2* Standard Error p DFP v. DFO 2.1 0.99 0.033 Comb v DFO 2.4 0.69 <0.001 DFX v DFO 0.44 0.82 0.6

Reduction of Hepatic Iron in Patients with Thalassemia Major According to Iron Chelation Regime Assessed by MRI T2*

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5410-5410
Author(s):  
Vassilios Ladis ◽  
Giorgos Chouliaras ◽  
Kirikos Zannikos ◽  
Panagiotis Moraitis ◽  
Eleni Berdoussi ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Linear Regression Analysis ◽  
Thalassemia Major ◽  
Rate Of Change ◽  
Hepatic Iron ◽  
Iron Loading ◽  
Liver Iron ◽  
Cardiac Iron ◽  
Iron Load ◽  
Number Of Patients

Abstract In 212 thalassemia major patients, repeated assessments for cardiac and hepatic iron (LIC) assessed by Magnetic Resonance Imaging (MRI – T2*) have been performed. The chelation regimes were either desferrioxamine (DFO), deferiprone (DFP), combination of DFO and DFP (Comb) or deferasirox (DFX). In general over the last few years, tailoring of chelation therapy has been principally guided by the cardiac iron loading. As many patients had been found to have excess cardiac iron, the majority (48%) had been placed on Comb. Patients were grouped according to the degree of siderosis. A T2* of &lt;1.6ms was regarded as heavy LIC, between 1.6–4.0 moderate, 4.1–9.0 mild and &gt; 9.1 acceptable. Taking into account that the change in T2* is not necessarily linear with respect to time and as the overall time of exposure to DFO, DFP and Comb regimes was significantly greater than that with DFX it was unjustified to perform comparative analysis using the total time period of the patients who were on any of the non DFX regimes. Therefore, to compare the efficacy of the four regimes on LIC, we performed an analysis using student T test to assess the rate of change only between the first and second MRI in patients with comparable LIC according to each chelation regime with adjustment for overall time of exposure (Table 1). Using the same data and applying linear regression analysis (Table 2) we compared the effect of DFO to the other three regimes in the annual rate of increasing hepatic T2*. Only Comb is effective at all levels of hepatic iron loading in reducing the iron content. DFX is effective in the mildly iron loaded patients and for the moderately iron loaded patients, its efficacy approaches statistical significance. DFP does not seem to significantly decrease LIC at any level of hepatic iron load however the numbers of patients in that group are very small. Interestingly DFO seems the least effective at all levels of hepatic iron loading and particularly in the heavy loaded patients. This factor may be related to poor compliance to its use as the patients who have reached such levels of iron load are more often those who are not compliant. In the comparison analysis to DFO, only Comb is significantly better and DFP and DFX are equivalent to it. In addition Comb is more effective than DFX and DFP in that over 12 months it would increase the T2* by 3.8ms (p &lt;0.001) and 3.9ms (p 0.012) respectively. DFX and DFP are similar in efficacy in that they maintain the liver iron at the same levels (DFP vDFX 0.009ms p=0.95). In patients with hepatic T2* &gt;9ms, 4 of 11 on DFO, 5 of 6 on DFX, 7 of 11 on DFP and 3 of 22 on Comb fell below 9. It is of note that DFO only maintains LIC and that a number of patients in the normal range increased LIC. Taking this data into account the DFX and DFP results are compatible with those seen both in the clinic and in trials. It is apparent however that combination therapy is the most effective regime for reducing hepatic iron significantly. As with cardiac iron loading, by knowing the degree of hepatic iron loading by the non-invasive T2* measurement and being able to manipulate patients chelation regimes, it seems possible to be able to have patients free of excess hepatic iron and potentially reduce other iron related morbidities as well. Table 1 Annual estimated mean change in T2* according to severity of hepatic siderosis Regime Heavy Moderate Mild ΔT2* p ΔT2** p ΔT2* p *tm= mean time (in months) between MRI studies DFO n= 42 tm*= 24.6 0.05 0.5 0.57 0.37 0.1 0.7 DFP n= 11 tm= 23.8 0.56 0.25 0.88 0.31 3.5 0.19 Comb n= 101 tm=21.7 1.17 0.0064 3.6 &lt;0.001 5.9 &lt;0.001 DFX n=58 tm=15.2 3.1 0.11 1.25 0.06 3.8 0.014 Table 3 Mean estimated difference in T2* Standard Error p DFP v. DFO −0.7 1.6 0.7 Comb v DFO 3.1 1.05 0.03 DFX v DFO −0.7 1.2 0.5

scholarly journals A Phase II Study of Nivolumab in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 467-467 ◽  
Author(s):  
N. Nora Bennani ◽  
Levi D Pederson ◽  
Pamela Atherton ◽  
Ivana Micallef ◽  
Joseph P. Colgan ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Interim Analysis ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Advisory Board ◽  
T Cell Lymphoma ◽  
Number Of Patients ◽  
Hyperprogressive Disease

Introduction: Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of mature aggressive T-cell non-Hodgkin lymphomas. They carry a worse prognosis for most subtypes compared with their B-cell counterparts. Despite the recent approval of newer therapies, the response rate and duration of clinical benefit is short and the outlook for patients with relapsed/refractory (RR) PTCL remains poor. There is therefore a need for novel effective therapies in PTCL. Targeting the profoundly immunosuppressive tumor microenvironment (TME) in PTCL is one such approach. Preclinical data show that malignant cells in PTCL overexpress programmed death ligand 1 (PD-L1), which signals via programmed death-1 (PD-1) receptor, and provides an inhibitory signal further suppressing antitumor immunity. PD-1/PD-L1/2 interactions in PTCL are particularly complicated as both the receptor and ligands can be expressed on the malignant T-cell. While the use of anti-PD-1 blocking antibodies has shown remarkable efficacy particularly in relapsed Hodgkin lymphoma, only a small number of patients with PTCL have been treated with checkpoint blockade. We conducted an investigator-initiated phase 2 prospective study of single-agent nivolumab for RR PTCL. We report here the results of the prespecified interim analysis. Study design and patient selection: Nivolumab was given at a flat dose of 240 mg intravenously (IV) every 2 weeks for 8 cycles then 480 mg IV every 4 weeks starting cycle 9. The primary objective was to assess the overall response rate (ORR) defined as proportion of subjects achieving either a partial response (PR) or complete response (CR) within 12 cycles of treatment. Secondary objectives were to assess safety and tolerability of nivolumab in PTCL and to assess progression-free survival (PFS), duration of response (DOR) and overall survival (OS). Pre-planned sample size was 39, assuming that an ORR of 10% or less would be considered negative and an ORR of 30% or greater would warrant further study. We used a one-stage design with an interim analysis (upon enrolling 12 subjects) based on a Simon optimal design to assess efficacy. This design had a 90% power with a 1-sided 10% level test. The Duffy and Santner method was utilized to determine confidence intervals for the ORR. Kaplan-Meier methods were used to assess PFS, OS, and DOR. This study was sponsored by Bristol-Myers Squibb (NCT03075553). Results: Twelve patients who received at least one cycle of nivolumab were included in this interim analysis. Patient characteristics are illustrated in table 1. Half (6/12) of the patients had angioimmunoblastic T-cell lymphoma (AITL), 3/12 had PTCL, not otherwise specified (NOS), one had ALK negative anaplastic large cell lymphoma (ALK- ALCL). Most (11/12) were advanced stage (stage 4), had extranodal disease and half of the patients had received a prior autologous transplant. The ORR was 33% (4/12) (95% CI: 12.3 - 63.7%): 1 CR seen in ALK-ALCL; 2 PR, 1 in PTCL, NOS and 1 in enteropathy associated T-cell lymphoma; 1 CR in AITL. The median DOR was 3.6 months (95% CI: 1.9-6.9). The median PFS for all 12 patients was short at 1.9 months (95% CI: 1.5-8.7); median OS was 7.9 months (95% CI: 3.4-10.8) (Panel A). Hyperprogressive disease (defined as dramatic progression within 1 cycle of treatment) occurred in 4 patients. Observed grade 3 and higher adverse events (AEs) were as follows: non-hematologic AEs in 5/12 (41.7%), while hematologic AEs were seen in 3/12 (25%) patients. Conclusions: Nivolumab had modest clinical activity in patients with R/R PTCL and the study met the criteria at interim analysis to continue accrual. However, due to the high number of patients with hyperprogressive disease, the moderate activity of the drug, and short DOR, a decision was made to halt the study. These findings likely reflect the distinct biology of PTCL and should be considered when designing future studies using checkpoint inhibitors in these diseases. Further studies are indicated using nivolumab in combination (rather than a single-agent) and use of biomarkers to better predict the responders. Disclosures Bennani: Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; Celgene: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Curis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding. Ansell:Merck: Other: research funding for clinical trials; Seattle Genetics: Other: research funding for clinical trials; Takeda: Other: research funding for clinical trials; Bristol Myers Squibb: Other: research funding for clinical trials; Regeneron: Other: research funding for clinical trials; Affimed: Other: research funding for clinical trials; Pfizer: Other: research funding for clinical trials; AI Therapeutics: Other: research funding for clinical trials.

Prevalence of treatment with glaucoma medication in Scotland, 2010–2017

2019 ◽  
Vol 104 (3) ◽  
pp. 381-385 ◽  
Author(s):  
Alan P Rotchford ◽  
John Hughes ◽  
Pankaj Kumar Agarwal ◽  
Andrew J Tatham
Keyword(s):  
Census Data ◽  
Population Changes ◽  
Expected Number ◽  
Glaucoma Medication ◽  
Size And Age Structure ◽  
Number Of Patients ◽  
Rate Of Increase ◽  
Demographic Distribution ◽  
Over 40 Years ◽  
Prescribing Information

AimsTo report the number and demographic distribution of patients receiving intraocular pressure (IOP)-lowering medications across the whole population of Scotland for the years 2010–2017 and, using national census data, show how the observed changes compare with those predicted by the increasing age of the population structure over this period.MethodsData were sourced from the Prescribing Information System of the NHS Information and Statistics Division for Scotland. The number of patients dispensed any IOP-lowering medication from a community pharmacy during each calendar year was collected by gender and by 5-year age bands. National census data were used to model the expected annual increase in treatment numbers due to population ageing.ResultsThe number of treated patients in 2017 was 61 249 which represents 1.13% of the whole population (or 2.16% over 40 years of age). The number increased from 48 178 in 2010—an increase over this period of 27.13% (3.88% per year).Prevalence increased with age, reaching 10.67% in those over 90 years. After age adjustment, more men were treated than women (OR 1.26).The expected number treated in 2017 based on census predictions was 54 075 (an increase of 5897 (12.24%) from 2010). The observed growth of 27.13% was 2.22-fold greater than the rate expected by population changes over the period 2010–2017.ConclusionThe number of patients on medication for glaucoma and ocular hypertension in Scotland is increasing. The rate of increase cannot be explained by changes in the size and age structure of the population alone.

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