Primary Outcome For Phase Research Articles

Imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumours of the lung and prostate: a phase 1/2, first-in-human trial

Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [89Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer. We conducted an open-label, first-in-human study of immunoPET-CT imaging with [89Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [89Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [89Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [89Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741. Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [89Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [89Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort. DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies. National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.

Peer mentorship to improve outcomes in patients on hemodialysis (PEER-HD): a randomized controlled trial protocol

BackgroundPatients receiving in-center hemodialysis experience disproportionate morbidity and incur high healthcare-related costs. Much of this cost stems from potentially avoidable hospitalizations. Peer mentorship has been used effectively to improve outcomes for patients with complex chronic diseases. We propose testing the efficacy of peer mentorship on hospitalization rates among patients receiving hemodialysis.MethodsThis is a multicenter parallel group randomized controlled pragmatic trial of patients treated at hemodialysis facilities in Bronx, NY and Nashville, TN. The study has two phases. Phase 1 will enroll and train 16 hemodialysis patients (10 in Bronx, NY and 6 in Nashville TN) to be mentors using a program focused on enhancing self-efficacy, dialysis self-management and autonomy-supportive communication skills. Phase 2 will enroll 200 high risk adults receiving hemodialysis (140 in Bronx, NY and 60 in Nashville, TN), half of whom will be randomized to intervention and half to usual care. Intervention participants are assigned to weekly telephone calls with trained mentors (see Phase 1) for a 3-month period.The primary outcome of Phase 1 will be engagement of mentors with training and change in knowledge scores and autonomy skills from pre- to post-training. The primary outcome of Phase 2 will be the composite count of ED visits and hospitalizations at the end of study follow-up in patient participants assigned to intervention as compared to those assigned to usual care. Secondary outcomes for Phase 2 include the change over the trial period in validated survey scores measuring perception of social support and self-efficacy, and dialysis adherence metrics, among intervention participants as compared to usual care participants.DiscussionThe PEER-HD study will test the feasibility and efficacy of a pragmatic peer-mentorship program designed for patients receiving hemodialysis on ED visit and hospitalization rates. If effective, peer-mentorship holds promise as a scalable patient-centered intervention to decrease hospital resource utilization, and by extension morbidity and cost, for patients receiving maintenance in-center hemodialysis.Trial registrationClinicaltrials.gov identifier: NCT03595748; 7/23/2018.Trial sponsorNational Institutes of Diabetes, Digestive and Kidney Disease (NIDDK) 5R18DK118471.FundingFunding for this study was provided by the National Institutes of Diabetes, Digestive and Kidney Disease: R18DK118471.Study statusThis is an ongoing study and not complete. We are still collecting data for observational follow-up on participants.Related articlesNo related articles for this study have been submitted to any journal.The study sponsor and funders had no role in the design, analysis or interpretation of this data. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Tandem cardiovascular system modelling and machine learning for improved heart failure phenotyping.

Tandem cardiovascular system modelling and machine learning for improved heart failure phenotyping.

Usability and Effectiveness of Immersive Virtual Grocery Shopping for Assessing Cognitive Fatigue in Healthy Controls: Protocol for a Randomized Controlled Trial.

BackgroundCognitive fatigue (CF) is a human response to stimulation and stress and is a common comorbidity in many medical conditions that can result in serious consequences; however, studying CF under controlled conditions is difficult. Immersive virtual reality provides an experimental environment that enables the precise measurement of the response of an individual to complex stimuli in a controlled environment.ObjectiveWe aim to examine the development of an immersive virtual shopping experience to measure subjective and objective indicators of CF induced by instrumental activities of daily living. MethodsWe will recruit 84 healthy participants (aged 18-75 years) for a 2-phase study. Phase 1 is a user experience study for testing the software functionality, user interface, and realism of the virtual shopping environment. Phase 2 uses a 3-arm randomized controlled trial to determine the effect that the immersive environment has on fatigue. Participants will be randomized into 1 of 3 conditions exploring fatigue response during a typical human activity (grocery shopping). The level of cognitive and emotional challenges will change during each activity. The primary outcome of phase 1 is the experience of user interface difficulties. The primary outcome of phase 2 is self-reported CF. The core secondary phase 2 outcomes include subjective cognitive load, change in task performance behavior, and eye tracking. Phase 2 uses within-subject repeated measures analysis of variance to compare pre- and postfatigue measures under 3 conditions (control, cognitive challenge, and emotional challenge).ResultsThis study was approved by the scientific review committee of the National Institute of Nursing Research and was identified as an exempt study by the institutional review board of the National Institutes of Health. Data collection will begin in spring 2021.ConclusionsImmersive virtual reality may be a useful research platform for simulating the induction of CF associated with the cognitive and emotional challenges of instrumental activities of daily living.Trial RegistrationClinicalTrials.gov NCT04883359; http://clinicaltrials.gov/ct2/show/NCT04883359International Registered Report Identifier (IRRID)PRR1-10.2196/28073

Technology-Enabled Person-Centered Mental Health Services Reform: Strategy for Implementation Science.

BackgroundHealth information technologies are being rapidly developed to improve the delivery of mental health care; however, a range of facilitators, barriers, and contextual conditions can impact the adoption and sustainment of these solutions. An implementation science protocol supports researchers to achieve primary effectiveness goals in relation to mental health services reform and aids in the optimization of implementation processes to promote quality health care, prolonging sustainability.ObjectiveThe aim of this paper is to describe our implementation science protocol, which serves as a foundation by which to systematically guide the implementation of technology-enabled solutions in traditional face-to-face and Web-based mental health services, allowing for revisions over time on the basis of retrospective review and constructive feedback from the services in which the technology-enabled solutions are implemented.MethodsOur implementation science protocol comprises four phases. The primary objective of the scoping and feasibility phase (Phase 1) is to determine the alignment between the service partner and the quality improvement goals supported by the technology-enabled solution. This is followed by Phase 2, the local co-design and preimplementation phase, which aims to utilize co-design methodologies, including service pathway modelling, participatory design, and user (acceptance) testing, to determine how the solutions could be used to enhance the service. In Phase 3, implementation, the accepted solution is embedded in the mental health service to achieve better outcomes for consumers and their families as well as health professionals and service managers. Using iterative evaluative processes throughout Phase 3, the solution is continuously developed, designed, and refined during implementation to adapt to the changing needs of the stakeholders, including consumers with lived experience and their families as well as the service. Thus, the primary outcome of Phase 3 is the optimized technology-enabled solution that can be maintained in a service during the sustainment and scalability phase (Phase 4) for the purposes of mental health services reform.ResultsFunding for the protocol was provided by the Australian Government Department of Health in June of 2017 for a period of 3 years. At the time of this publication, the protocol had been initiated in 11 services, serving three populations, all of which are currently operating in Phase 3. The first results are expected to be submitted for publication in 2020.ConclusionsWith the aim of improving mental health service quality, our implementation science protocol aids in the identification of factors that predict the likelihood of implementation success, as well as the development of strategies to proactively mitigate potential barriers to achieve better implementation outcomes. Putting in place a theoretically sound implementation science protocol is essential to facilitate the uptake of novel technology-enabled solutions and evidence-based practices into routine clinical practice for the purposes of improved outcomes.

Joint modeling of progression-free and overall survival and computation of correlation measures.

In this paper, we derive the joint distribution of progression-free and overall survival as a function of transition probabilities in a multistate model. No assumptions on copulae or latent event times are needed and the model is allowed to be non-Markov. From the joint distribution, statistics of interest can then be computed. As an example, we provide closed formulas and statistical inference for Pearson's correlation coefficient between progression-free and overall survival in a parametric framework. The example is inspired by recent approaches to quantify the dependence between progression-free survival, a common primary outcome in Phase 3 trials in oncology and overall survival. We complement these approaches by providing methods of statistical inference while at the same time working within a much more parsimonious modeling framework. Our approach is completely general and can be applied to other measures of dependence. We also discuss extensions to nonparametric inference. Our analytical results are illustrated using a large randomized clinical trial in breast cancer.

Comparative Efficacy of Therapies for Treatment of Depression for Patients Undergoing Maintenance Hemodialysis: A Randomized Clinical Trial.

Although depression is common among patients receiving maintenance hemodialysis, data on their acceptance of treatment and on the comparative efficacy of various therapies are limited. To determine the effect of an engagement interview on treatment acceptance (phase 1) and to compare the efficacy of cognitive behavioral therapy (CBT) versus sertraline (phase 2) for treating depression in patients receiving hemodialysis. Multicenter, parallel-group, open-label, randomized controlled trial. (ClinicalTrials.gov: NCT02358343). 41 dialysis facilities in 3 U.S. metropolitan areas. Patients who had been receiving hemodialysis for at least 3 months and had a Beck Depression Inventory-II score of 15 or greater; 184 patients participated in phase 1, and 120 subsequently participated in phase 2. Engagement interview versus control visit (phase 1) and 12 weeks of CBT delivered in the dialysis facility versus sertraline treatment (phase 2). The primary outcome for phase 1 was the proportion of participants who started depression treatment within 28 days. For phase 2, the primary outcome was depressive symptoms measured by the Quick Inventory of Depressive Symptoms-Clinician-Rated (QIDS-C) at 12 weeks. The proportion of participants who initiated treatment after the engagement or control visit did not differ (66% vs. 64%, respectively; P= 0.77; estimated risk difference, 2.1 [95% CI, -12.1 to 16.4]). Compared with CBT, sertraline treatment resulted in lower QIDS-C depression scores at 12 weeks (effect estimate, -1.84 [CI, -3.54 to -0.13]; P= 0.035). Adverse events were more frequent in the sertraline than the CBT group. No randomized comparison was made with no treatment, and persistence of treatment effect was not assessed. An engagement interview with patients receiving maintenance hemodialysis had no effect on their acceptance of treatment for depression. After 12 weeks of treatment, depression scores were modestly better with sertraline treatment than with CBT. Patient-Centered Outcomes Research Institute, Dialysis Clinic, Kidney Research Institute, and National Institute of Diabetes and Digestive and Kidney Diseases.

Laparoscopic versus open pancreatoduodenectomy for pancreatic or periampullary tumours (LEOPARD-2): a multicentre, patient-blinded, randomised controlled phase 2/3 trial

Laparoscopic pancreatoduodenectomy may improve postoperative recovery compared with open pancreatoduodenectomy. However, there are concerns that the extensive learning curve of this complex procedure could increase the risk of complications. We aimed to assess whether laparoscopic pancreatoduodenectomy could reduce time to functional recovery compared with open pancreatoduodenectomy. This multicentre, patient-blinded, parallel-group, randomised controlled phase 2/3 trial was performed in four centres in the Netherlands that each do 20 or more pancreatoduodenectomies annually; surgeons had to have completed a dedicated training programme for laparoscopic pancreatoduodenectomy and have done 20 or more laparoscopic pancreatoduodenectomies before trial participation. Patients with a benign, premalignant, or malignant indication for pancreatoduodenectomy, without signs of vascular involvement, were randomly assigned (1:1) to undergo either laparoscopic or open pancreatoduodenectomy using a central web-based system. Randomisation was stratified for annual case volume and preoperative estimated risk of pancreatic fistula. Patients were blinded to treatment allocation. Analysis was done according to the intention-to-treat principle. The main objective of the phase 2 part of the trial was to assess the safety of laparoscopic pancreatoduodenectomy (complications and mortality), and the primary outcome of phase 3 was time to functional recovery in days, defined as all of the following: adequate pain control with only oral analgesia; independent mobility; ability to maintain more than 50% of the daily required caloric intake; no need for intravenous fluid administration; and no signs of infection (temperature <38·5°C). This trial is registered with Trialregister.nl, number NTR5689. Between May 13 and Dec 20, 2016, 42 patients were randomised in the phase 2 part of the trial. Two patients did not receive surgery and were excluded from analyses in accordance with the study protocol. Three (15%) of 20 patients died within 90 days after laparoscopic pancreatoduodenectomy, compared with none of 20 patients after open pancreatoduodenectomy. Based on safety data from the phase 2 part of the trial, the data and safety monitoring board and protocol committee agreed to proceed with phase 3. Between Jan 31 and Nov 14, 2017, 63 additional patients were randomised in phase 3 of the trial. Four patients did not receive surgery and were excluded from analyses in accordance with the study protocol. After randomisation of 105 patients (combining patients from both phase 2 and phase 3), of whom 99 underwent surgery, the trial was prematurely terminated by the data and safety monitoring board because of a difference in 90-day complication-related mortality (five [10%] of 50 patients in the laparoscopic pancreatoduodenectomy group vs one [2%] of 49 in the open pancreatoduodenectomy group; risk ratio [RR] 4·90 [95% CI 0·59-40·44]; p=0·20). Median time to functional recovery was 10 days (95% CI 5-15) after laparoscopic pancreatoduodenectomy versus 8 days (95% CI 7-9) after open pancreatoduodenectomy (log-rank p=0·80). Clavien-Dindo grade III or higher complications (25 [50%] of 50 patients after laparoscopic pancreatoduodenectomy vs 19 [39%] of 49 after open pancreatoduodenectomy; RR 1·29 [95% CI 0·82-2·02]; p=0·26) and grade B/C postoperative pancreatic fistulas (14 [28%] vs 12 [24%]; RR 1·14 [95% CI 0·59-2·22]; p=0·69) were comparable between groups. Although not statistically significant, laparoscopic pancreatoduodenectomy was associated with more complication-related deaths than was open pancreatoduodenectomy, and there was no difference between groups in time to functional recovery. These safety concerns were unexpected and worrisome, especially in the setting of trained surgeons working in centres performing 20 or more pancreatoduodenectomies annually. Experience, learning curve, and annual volume might have influenced the outcomes; future research should focus on these issues. Grant for investigator-initiated studies by Johnson & Johnson Medical Limited.

Administration of Albumin Solution Increases Serum Levels of Albumin in Patients With Chronic Liver Failure in a Single-Arm Feasibility Trial

Background & AimsInfections are life-threatening to patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF). Patients with AD/ACLF have prostaglandin E2–mediated immune suppression, which can be reversed by administration of albumin; infusion of 20% human albumin solution (HAS) might improve outcomes of infections. We performed a feasibility study to determine optimal trial design, assess safety, and validate laboratory assessments of immune function to inform design of a phase 3 trial.MethodsWe performed a prospective multicenter, single-arm, open-label trial of 79 patients with AD/ACLF and levels of albumin lower than 30 g/L, seen at 10 hospitals in the United Kingdom from May through December 2015. Patients were given daily infusions of 20% HAS, based on serum levels, for 14 days or until discharge from the hospital. Rates of infection, organ dysfunction, and in-hospital mortality were recorded. The primary end point was daily serum albumin level during the treatment period. Success would be demonstrated if 60% achieved and maintained serum albumin levels at or above 30 g/L on at least one third of days with recorded levels.ResultsThe patients’ mean model for end-stage disease score was 20.9 ± 6.6. The primary end point (albumin ≥30 g/L on at least one third of days recorded) was achieved by 68 of the 79 patients; 75% of administrations were in accordance with suggested dosing regimen. Mean treatment duration was 10.3 days (104 ± 678 mL administered). There were 8 deaths and 13 serious adverse events, considered by the independent data-monitoring committee to be consistent with those expected. Twelve of 13 patients that developed either respiratory or cardiovascular dysfunction (based on ward-based clinical definitions) as their only organ dysfunction were alive at 30 days compared with 1 of 3 that developed renal dysfunction. Only 1 case of brain dysfunction was recorded.ConclusionsIn a feasibility trial, we found that administration of HAS increased serum levels of albumin in patients with AD/ACLF. The dosing regimen was acceptable at multiple sites and deemed safe by an independent data-monitoring committee. We also developed a robust system to record infections. The poor prognosis for patients with renal dysfunction was confirmed. However, patients with cardiovascular or respiratory dysfunction had good outcomes, which is counterintuitive. Severe encephalopathy appeared substantially under-reported, indicating that ward-based assessment of these parameters cannot be recorded with sufficient accuracy for use as a primary outcome in phase 3 trials. Trial registration no: EudraCT 2014-002300-24 and ISRCTN14174793.

Phase I/II trial of cetuximab with 5-fluorouracil and mitomycin C concurrent with radiotherapy in patients with muscle invasive bladder cancer.

4527 Background: This phase I/II trial assessed the safety, feasibility and efficacy of cetuximab (Cet) in combination with 5-fluorouracil (5FU) and mitomycin C (MMC) with concurrent radiotherapy (RT) for the treatment of muscle invasive bladder cancer (MIBC). BC2001 trial has previously reported significant improvement in locoregional control in patients (pts) with MIBC who were randomised to synchronous chemo-RT compared to RT alone (James, Hussain, Hall et al NEJM 2012). Results for phase I have been reported previously. This abstract reports the combined results of phases I/II. Methods: From September 2012 to October 2016, 33 pts were recruited (7 pts to phase I from 2 UK centres and 26 patients to phase II from 5 UK centres). Pts received loading dose of Cet 400 mg/m2 followed by weekly Cet 250 mg/m2 for 7 weeks, continuous infusion 5FU 500mg/m2/day during fractions 1-5 and 16-20 of RT and MMC 12mg/m2on day 1 in combination with radical RT 64 Gy in 32 fractions. Neoadjuvant chemotherapy was mandatory in phase I but optional in phase II. Primary outcomes in phase I were feasibility and toxicity. Primary outcome in phase II was 3 month pathological complete response (CR) rate, secondary outcomes included toxicity, progression free survival (PFS) and overall survival (OS). Results: Median age of pts was 70 (range 46.9-85.6). Treatment completion rates in phase I were RT 100%, 5FU 100 %, MMC 100%, Cet 96%. Of the 28 analysable pts, phase II primary outcome data was available for 25 pts at the time of analysis with a 3 month pathological CR rate of 88%. 5 local progressions and 4 deaths were reported. 12 pts suffered at least one SAE. Grade 4 toxicities observed were dyspnoea, atrial fibrillation, interstitial pneumonitis, sepsis, thromboembolism, neutropenia and palpitations. The commonest grade 3 toxicities were skin rash, diarrhoea, low platelet count, low white blood cell count, fever and haematuria. The most common grade 1 and 2 toxicities were diarrhoea and skin rash. Data on PFS and OS will be presented. Conclusions: It was feasible and safe to add cetuximab to full dose chemo-RT with 5FU/MMC. The CR rate is encouraging and further randomised studies with this combination are warranted. Clinical trial information: ISRCTN80733590.

A 20 years of progress and future of quantitative magnetic resonance imaging (qMRI) of cartilage and articular tissues-personal perspective.

In 1994, the first article on quantitative magnetic resonance imaging (qMRI) of articular cartilage was published, and tremendous progress in image acquisition, image analysis, and applications has since been made. The objective of this personal perspective is to highlight milestones in the field of qMRI of cartilage and other articular tissues over these past 20 years. Based on a Pubmed search of original articles, the authors selected 30 articles which they deemed to be among the first to provide an important technological step forward in qMRI of cartilage, provided a first application in a particular context, or provided mechanistic insight into articular cartilage physiology, pathology, or treatment. This personal perspective summarizes results from these 30 articles. Further, the authors provide examples of how qMRI of cartilage has translated to quantitative analysis approaches of other articular tissues, including bone, meniscus, and synovium/edema. Eventually, the report provides a summary of how the lessons learned might be applied to future clinical trials and clinical practice. Over the past 20 years, quantitative imaging of articular tissues has emerged from a method to a dynamic field of research by its own. Continuing the qMRI biomarker qualification process will be crucial in convincing regulatory agencies to accept these as primary outcomes in phase 3 intervention trials. Once successful structural intervention will actually become available in OA, qMRI biomarkers may play an essential role in monitoring response to therapy in the clinic, and in stratifying disease phenotypes that respond differently to treatment.

Primary Outcomes in Phase 2 Study of Hypofractionated Patterns by Stereotactic Ablative Radiation Therapy (SABR)

Primary Outcomes in Phase 2 Study of Hypofractionated Patterns by Stereotactic Ablative Radiation Therapy (SABR)

Reporting Trends of Outcome Measures in Phase II and Phase III Trials Conducted in Advanced-Stage Non-small-cell Lung Cancer

The methodology of conducting clinical trials in lung cancer has been challenged by the particular characteristics of new targeted agents. Thus, the choice of correct outcome measures and selection of best study designs are essential. We assessed the trends in reporting of outcome measures in phase II and phase III trials conducted in advanced non-small-cell lung cancer (NSCLC) patients. Data from September 2000 to September 2012 were extracted from the ClinicalTrials.gov database, and a descriptive-comparative analysis was performed to evaluate outcome-measures reporting for the two phases. We identified 459 phase II and 128 phase III trials that met our inclusion criteria. The frequently reported primary outcomes in phase II trials were progression-free survival (PFS; 32%), response rate (RR; 21.4%), and safety and toxicity (adverse events [AEs]; 14.6%). In contrast, overall survival (OS; 60.9%) and PFS (26.6%) were frequently reported primary outcomes in phase III trials. AEs were reported as a secondary outcome measure in 50.1 and 64.8% of phase II and phase III trials, respectively. Improvement in quality of life was identified as a secondary outcome measure significantly more frequently in phase III than in phase II trials. Our study identified recent trends in reports of outcome measures in advanced-stage NSCLC phase II and phase III trials. The outcomes of this study can be valuable for investigators with minimal or some experience in the field of oncology who are conducting clinical research.

SEEING INJECTABLE MS THERAPIES DIFFERENTLY: THEY ARE MORE SIMILAR THAN DIFFERENT

Conventional MRI is a sensitive tool to identify focal white matter inflammation in patients with multiple sclerosis (MS). Despite a limited correlation between MRI lesions and relapses in untreated individuals,1 gadolinium-enhancing lesion activity correlates with treatment response,2 and predicts relapse outcomes in phase III clinical trials.3 For this reason, new lesions on MRI are the standard primary outcome of phase II clinical trials in relapsing-remitting MS (RRMS). The potential use of MRI biomarkers to compare different MS therapies to each other is also attractive. Comparison of the results of different pivotal trials, although dangerous, has suggested to some that high-dose, high-frequency administration of interferon-β (IFNβ) may have a faster onset of action than glatiramer acetate (GA). This has led to speculation that IFNβ may be more effective than GA, at least in the early stages of treatment. In this issue of Neurology ®, Cadavid et al.4 report the results of the BECOME trial, a head-to-head comparison which sought to address this question. In this industry-sponsored, investigator-conducted trial, 75 patients with RRMS were randomized to receive …

Imaging outcomes for neuroprotection and repair in multiple sclerosis trials

Multiple sclerosis (MS) is commonly regarded as an inflammatory disease, but it also has a neurodegenerative component, which represents an additional target for treatment. The use of MRI to evaluate the inflammatory disease component in 'proof-of concept' clinical trials is well established, but no systematic assessment of imaging outcomes to evaluate neuroprotection or repair in MS has been performed. In this Review, we examine the potential of traditional and novel imaging parameters to serve as primary outcomes in phase II clinical trials of neuroprotective and reparative strategies in MS. We present the conclusions of an international meeting of imaging, clinical and statistical experts, as well as a review of relevant literature. The available imaging techniques are appraised in five categories of performance: pathological specificity, reproducibility, sensitivity to change, clinical relevance, and response to treatment. At present, the three most promising primary outcomes in phase II trials of neuroprotective and/or reparative strategies in MS are: changes in whole-brain volume to gauge general cerebral atrophy; T1 hypointensity and magnetization transfer ratio to monitor the evolution of lesion damage; and optical coherence tomography findings to evaluate the anterior visual pathway. Power calculations show that these outcome measures can be applied with attainable sample sizes.

Quality of Reporting Primary Outcomes in Phase II Cancer Trials

Quality of Reporting Primary Outcomes in Phase II Cancer Trials

Picturing Multiple Sclerosis: Conventional and Diffusion Tensor Imaging

Magnetic resonance imaging (MRI) has provided an unparalleled window into understanding multiple sclerosis (MS). Through recognition of relatively specific characteristics of MS, MRI has become an integral part of patient initial evaluation and long-term management. MRI has now been integrated into the formal diagnostic criteria, whereby new lesions can fulfill either dissemination in space or dissemination in time criteria. Long-term MS therapies significantly reduce the development of new lesions as measured by MRI, and clinical trial methodology now routinely uses MRI as the primary outcome in Phase I/II MS trials. Despite the advantages provided by MRI, conventional imaging indicates only the presence of injury to the central nervous system, providing little information on either the severity of injury or its later recovery. Several advanced imaging methodologies such as diffusion tensor imaging (DTI) provide a greater dynamic range for evaluating tissue integrity. DTI has provided useful insights into the pathogenesis of MS, both within lesions as well as within the white matter which appears normal on conventional imaging. Evidence from animal models suggests that DTI may differentiate axonal injury from demyelination and therefore may be useful in the evaluation of neuroprotective therapies.

Surrogate endpoints in neoadjuvant rectal cancer trials: Statistical evaluation using data from the FFCD 9203 trial

4086 Background: Neo-adjuvant rectal cancer trials use overall survival (OS) and local control as standard endpoints. Using earlier endpoints as primary outcomes in phase III trials requires them to be validated as surrogates for OS or local control. The aim of this study was to evaluate the statistical validity of specimen sterilization, pT and pN stages and circumferential resection margin as surrogate endpoints for OS and local recurrence free survival (LRFS). Methods: We used data from the FFCD 9203 trial (Gérard et al. J Clin Oncol 2006): preoperative radiotherapy (RT) vs preoperative chemoradiation (CT-RT) in T3–4 rectal cancers. Based on logistic regressions and Cox proportional hazards regression models we applied single-trial validation methods: Prentice criteria, proportion of treatment effect explained (PTE), relative effect, adjusted association and the proportion of variation explained (R²). OS was defined as time interval between randomization and death (all causes) and LRFS as time interval between randomization and local recurrence. Survival curves were estimated using Kaplan-Meier method and compared using Log-Rank tests. Results: Our analyses were based on the 742 eligible patients of the trial (367 patients in the RT arm and 375 in the CT-RT arm). Complete sterilization of the operative specimen was more frequent in the CT-RT arm (11.4% vs 3.6%, p<.0001) and the 5-year local recurrence rate was significantly lower (16.5% vs 8.1%, p=0.004) while the 5-year OS did not differ (67.9% vs 67.4%, p=0.69). None of the variables fulfilled the four Prentice criteria whatever final endpoint. The most surrogate variable was specimen sterilization categorized as pT0 or few residual cells (S1) vs evolutive residual cells (S0). It explained 12% of the effect of treatment on LRFS (PTE=0.119) but the lower bound of the 95% CI was under the critical limit of 0.5. After adjusting for treatment, relative risk of local recurrence (S1 vs S0) was 0.56 (95% CI [0.28–1.10], p=0.09, R²=0.05). With OS as final endpoint, PTE for sterilization was not interpretable (PTE=-249.3%). Conclusions: Our data did not allow validating relevant surrogates for long term outcomes in neo- adjuvant rectal cancer trials. To increase power, an individual meta-analysis is planned. No significant financial relationships to disclose.