Era Of Clinical Trials Research Articles

Optimising remote sampling of NfL and GFAP using blood cards in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort

AbstractBackgroundIn recent years, blood‐based biomarkers have become key measures in the study of dementia, including frontotemporal dementia (FTD), with use in diagnosis and clinical trial outcomes. Remote collection of blood samples provides a more accessible and cost‐effective alternative to regular clinic visits and allows for more frequent measures to be taken. This is particularly relevant as we progress into an era of clinical trials in FTD. The aim of this current study was to assess whether neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), markers previously shown be increased in genetic forms of FTD, can be measured using dried blood cards and to optimise the protocol for this.Method10 participants from the University College London GENFI study (three C9orf72 mutation carriers, four GRN mutation carriers and three mutation negative controls) were included in this pilot study. Blood samples were collected by venepuncture from each participant: one sample for plasma analysis and one sample which was used to pipette whole blood on to a blood card. NfL and GFAP concentrations were subsequently quantified using the Simoa multiplex Neurology 4‐Plex A (N4PA) assay in both plasma and the dried blood card. Total protein concentration was measured with the Bradford protein assay and used to correct for variable concentrations of blood card spots. The effect of incubation temperature and time as well as freeze thaw cycles were also assessed as part of the optimisation process.ResultIn this pilot cohort, blood card GFAP concentration (BSA corrected) very strongly correlated with matched plasma GFAP (r = 0.897, p = 0.0004), whilst blood card NfL concentration (BSA corrected) strongly correlated with matched plasma NfL (r = 0.721, p = 0.0234). Incubation temperature impacted total protein concentration in the blood cards, but freeze‐thaw and incubation time did not.ConclusionThis pilot study shows that NfL and GFAP concentrations can be successfully quantified using dried blood cards and results strongly correlate with plasma measures. Future work will involve investigating whether these biomarkers can be measured in blood cards obtained with capillary blood through lancet‐based fingerprick collection and assessing the feasibility of home collection.

Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials.

The development of new possible treatments for C9orf72-related ALS and the possibility of early identification of subjects genetically at risk of developing the disease is creating a critical need for biomarkers to track neurodegeneration that could be used as outcome measures in clinical trials. Current candidate biomarkers in C9orf72-ALS include neuropsychology tests, imaging, electrophysiology as well as different circulating biomarkers. Neuropsychology tests show early executive and verbal function involvement both in symptomatic and asymptomatic mutation carriers. At brain MRI, C9orf72-ALS patients present diffuse white and grey matter degeneration, which are already identified up to 20 years before symptom onset and that seem to be slowly progressive over time, while regions of altered connectivity at fMRI and of hypometabolism at [18F]FDG PET have been described as well. At the same time, spinal cord MRI has also shown progressive decrease of FA in the cortico-spinal tract over time. On the side of wet biomarkers, neurofilament proteins are increased both in the CSF and serum just before symptom onset and tend to slowly increase over time, while poly(GP) protein can be detected in the CSF and probably used as target engagement marker in clinical trials.

P.300Diaphragm imaging in Duchenne muscular dystrophy (DMD)

Reliable outcome measures able to demonstrate specific trends of disease progression are essential in this era of clinical trials in DMD. Magnetic resonance imaging (MRI) is increasingly being used to assess muscular degeneration in dystrophic patients. We studied muscle diaphragm through MRI and correlated MRI measurements of diaphragm structure and function with compartmental tidal volumes measured by opto-electronic plethysmography (OEP) and pulmonary function tests. 26 DMD patients and 12 age-matched controls were acquired in breath-hold on a 3T-scanner at full-expiration (EXP) and full-inspiration (INSP), by a multi-point gradient echo Dixon sequence. We measured: 1) cranio-caudal diaphragmatic excursion as the median vertical distance between the EXP and INSP diaphragm surfaces; 2) muscle fatty infiltration as the amount of intramuscular adipose tissue in regions of interest. DMD patients and controls were also acquired during quiet breathing in supine posture by OEP; ribcage and abdominal volume variations were measured and expressed as percentage contribution to tidal volume. Cranio-caudal excursion of the diaphragm correlated positively to abdominal volume variation (r=0.61, p=0.0001) and negatively to rib cage volume variation (r=-0.60, p=0.0002). Diaphragm excursion decreased with decreasing FEV1 %pred (r=0.78, p<0.0001) and FVC %pred (r=0.76, p<0.0001). Fatty infiltration increased with decreasing FEV1 %pred (r=-0.88, p<0.0001) and FVC %pred (r=-0.88, p<0.0001). The progressive structure and function impairment of the diaphragm is highly related to compartmental tidal volumes and to pulmonary function tests.

How Cancer Patients Perceive Clinical Trials (CTs) in the Era of CTs: Current Perception and Its Differences Between Common and Rare Cancers.

Perception has recently been highlighted as a critical determinant for participation in clinical trials (CTs) among cancer patients. We evaluated cancer patients' current perceptions of CTs using the PARTAKE questionnaires, focusing on differences between patients with common and rare cancers. From November 2015 to May 2017, we prospectively surveyed patients who had received anti-cancer treatment at Asan Medical Center. Among 333 respondents, 70.9% had common and 29.1% had rare cancers. In the cohort, 87.7% of patients with common cancers and 75.3% of patients with rare cancers answered that they heard of and knew about CTs. However, willingness to participate in CTs was expressed only in approximately 56% of patients, althoughit was significantly associated with awareness and perception. Surprisingly, patients with rare cancers when compared with patients with common cancers showed significantly lower levels of awareness and perception (64.2% vs 79.9%, p = 0.003 and 77.3% vs 91.9%, p < 0.001), and consequently less willingness to participate in CTs (47.4% vs 58.9%, p = 0.06). In addition, cancer patients still harbored fear and concerns about safety and rewardof CTs, and demonstrated substantial lack of knowledge about the voluntary nature of CTs, which was more obvious in patients with rare cancers. We identified relatively modest willingness of cancer patients to participate in CTs regardless of generally favorable perception. These findings are highlighted by the more negative perception of CTs among patients with rare cancers relative to those with common cancers. Further education and encouragement by research and public entities seem essential to improve motivation of CTs in cancer patients beyond good perception, especially for patients with rare cancers.

Influence of Enzalutamide on Cabazitaxel Pharmacokinetics: a Drug-Drug Interaction Study in Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients.

Purpose: In ongoing clinical research on metastatic castration-resistant prostate cancer (mCRPC) treatment, the potential enhanced efficacy of the combination of taxanes with AR-targeted agents, that is, enzalutamide and abiraterone, is currently being explored. Because enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme, a potential drug-drug interaction needs to be investigated.Experimental Design: Therefore, we performed a pharmacokinetic cross-over study in mCRPC patients who were scheduled for treatment with cabazitaxel Q3W (25 mg/m2). Patients were studied for three consecutive cabazitaxel cycles. Enzalutamide (160 mg once daily) was administered concomitantly after the first cabazitaxel cycle, during 6 weeks. Primary endpoint was the difference in mean area under the curve (AUC) between the first (cabazitaxel monotherapy) and third cabazitaxel cycle, when enzalutamide was added.Results: A potential clinically relevant 22% (95% CI, 9%-34%; P = 0.005) reduction in cabazitaxel exposure was found with concomitant enzalutamide use. The geometric mean AUC0-24h of cabazitaxel was 181 ng*h/mL (95% CI, 150-219 ng*h/mL) in cycle 3 and 234 ng*h/mL (95% CI, 209-261 ng*h/mL) in cycle 1. This combination did not result in excessive toxicity, whereas PSA response was promising.Conclusions: We found a significant decrease in cabazitaxel exposure when combined with enzalutamide. In an era of clinical trials on combination strategies for mCRPC, it is important to be aware of clinically relevant drug-drug interactions. Because recent study results support the use of a lower standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be substantial, because the addition of enzalutamide may result in subtherapeutic cabazitaxel exposure. Clin Cancer Res; 24(3); 541-6. ©2017 AACR.

Abstract 109: Trevo 2000: Results of the Largest Real-World Registry for Stent Retriever for Acute Ischemic Stroke

Objective: The Trevo Registry was designed to assess real world outcomes of the Trevo Retriever in patients experiencing ischemic stroke. It is the largest prospective study for acute stroke intervention, with 2010 patients enrolled and 90 day outcomes in 1873 patients. The primary endpoint is revascularization status based on post-procedure TICI score and secondary endpoints include 90-day mRS, 90-day mortality, neurological deterioration at 24 hours and device/procedure related adverse events. Methods: The study was a prospective, open-label, consecutive enrollment, multi-center, international registry of patients who underwent mechanical thrombectomy for acute stroke using the Trevo stent retriever as the initial device. Results: The median NIHSS at admission was 16 (IQR 11-20). Most patients (70.8%) were treated at &lt;= 6 hours from last known normal with a median procedure time of 50 minutes (32-77). The occlusion site was M1 or M2 in 73.9%. General anesthesia was employed in 43.5% of procedures. TICI 2b or 3 revascularization was 92.8% with an average of 1.7 passes with the device. Median NIHSS at 24 hours and discharge was 6 and 4 respectively. Fifty-five percent (55.2%) of patients had mRS ≤2 at 3 months and the overall mortality rate was 13.8%. Patients treated after 8 hours of symptom onset had a 95% revascularization rate and 51.2% mRS ≤2 at 3 months. The symptomatic ICH rate was 1.6%. Patients who met the revised AHA criteria for thrombectomy were found to have 59.5% mRS 0-2 at 90 days. Conclusions: The Trevo Retriever Registry represents the first real world data with stent retriever use in the era of clinical trials showing the overwhelming benefit of stent retrievers to treat acute ischemic stroke. Due to the fact that this data represents real world use of the Trevo Retriever, (e.g. subjects pre-stroke mRS &gt;1 (29%) and those treated 6-24 hours after stroke symptoms (29%), this data cannot be compared to the results from recent trials with restricted eligibility criteria. Future subgroup analysis of this large cohort will help to identify areas of future research to enhance outcomes further with this treatment modality.

369 The TREVO Registry-Subgroup Analysis, Treatment Beyond 6 Hours

Abstract INTRODUCTION Current randomized trials demonstrating superiority of mechanical thrombectomy for the treatment of acute ischemic stroke for anterior circulation large vessel occlusion, have enrolled patients with symptom onset up to 6 hours. Outcomes of thrombectomy beyond 6 hours have not been well studied. The Trevo Registry is designed to assess real world outcomes of the Trevo Retriever in patients experiencing acute ischemic stroke. Trevo registry has currently enrolled 1431 patients with 90-day outcome data. Outcomes of patients treated beyond 6 hours of symptom onset were studied. METHODS The study design is a prospective, open-label, consecutive enrollment, multi-center, global registry of all patients who undergo mechanical thrombectomy for acute stroke using the Trevo stent retriever as the initial device. Enrollment is expected to reach 2000 subjects at up to 100 sites. Subgroup analysis of enrolled patients treated beyond 6 hours of symptom onset and with 90-day follow-up was performed. RESULTS &gt;As of March 24, 2017, a total of 1846 total patients were enrolled. Median NIHSS at admission was 15.5 (IQR 11–20). The majority of patients (67.4%) were treated at 6 hours or less from last known normal with a median procedure time of 50 minutes (8-286 minutes). In patients treated after 6 hours from time last known well, the revascularization rate was 93.7% with symptomatic ICH of 1.8% and 90-day mRS = 2 was 51.8%. Subgroup analysis of patients presenting within 6 hours and those presenting beyond 6 hours showed no significant difference in patient demographics or medical comorbidities. There was no difference in complication rate or 90-day outcome between the two groups. CONCLUSION The Trevo Retriever Registry represents the first look at real world data with stent retriever use in the era of clinical trials showing the overwhelming benefit of stent retrievers to treat acute ischemic stroke. This data represents real world use of the Trevo Retriever including those treated beyond 6 hours after stroke symptoms (33.8%), and this data adds to the results from recent trials with restricted eligibility criteria.

Abstract WMP2: Trevo 2000: Real-World Experience in the First 1247 Patients

Objective: The Trevo Registry is designed to assess real world outcomes of the Trevo Retriever in patients experiencing ischemic stroke. This is the largest prospective study for acute stroke intervention, with 1247 patients currently enrolled and 90 day outcomes in 1021 patients. The primary endpoint is revascularization status based on post-procedure TICI score and secondary endpoints include 90-day mRS, 90-day mortality, neurological deterioration at 24 hours and device/procedure related adverse events. Methods: The study is a prospective, open-label, consecutive enrollment, multi-center, international registry of patients undergoing mechanical thrombectomy for acute stroke using the Trevo stent retriever as the initial device. Enrollment is expected to reach 2000 subjects at up to 100 sites. Results: As of August 13, 2016 a total of 1247 patients were enrolled. The median NIHSS at admission was 16 (IQR 11-20). Most patients (66.2%) were treated at &gt;/= 6 hours from last known normal with a median procedure time of 50 minutes (32-77). The occlusion site was M1 or M2 in 74.5%. General anesthesia was employed in 46.6% of procedures. TICI 2b or 3 revascularization was 92.8% with an average of 1.6 passes with the device. Median NIHSS at 24 hours and discharge was 6 and 4 respectively. Fifty-five percent of patients had mRS ≤2 at 3 months and the overall mortality rate was 15.4%. Patients treated after 8 hours of symptom onset had a 94.9% revascularization rate and 52.8% mRS ≤2 at 3 months. The symptomatic ICH rate was 1.2%. Patients who met the revised AHA criteria for thrombectomy were found to have 58.4% mRS 0-2 at 90 days. Conclusions: The Trevo Retriever Registry represents the first real world data with stent retriever use in the era of clinical trials showing the overwhelming benefit of stent retrievers to treat acute ischemic stroke. Due to the fact that this data represents real world use of the Trevo Retriever, (e.g. subjects pre-stroke mRS &gt;1 (16.5%) and those treated 6-24 hours after stroke symptoms (33.8%), this data cannot be compared to the results from recent trials with restricted eligibility criteria. Future subgroup analysis of this large cohort will help to identify areas of future research to enhance outcomes further with this treatment modality.

Tragedies in Clinical Trials - A History Wrapped Up

Today foremost emphasis is being given to the protection of patient's safety and ethics during the conduct of clinical trials. Serious considerations by regulatory authorities are taken to safeguard the patient's right, safety and wellbeing involved in a clinical trial. In addition considerations like International Conference on Harmonization (ICH) guidelines, Investigational New Drug (IND) application, New Drug Application (NDA), Post Marketing Surveillance (PMS) and Periodic Benefit-Risk Evaluation Report (PBRER) formerly known as Periodic Safety Update Report (PSUR) submissions to different regulatory authorities has also been framed to strengthen ethics and patient's safety. However modern clinical trials have evolved through serious consequences and tragedies like Thalidomide Tragedy, Sulfanilamide Disaster, Clioquinolol Tragedy, etc. associated with high morbidity and mortality. Potential reasons behind these tragedies include unethical clinical practices, inadequate preclinical safety and efficacy data, non-scientific conduct, lack of attentiveness for patient care, misinterpretation of safety data, lack of pharmaco-vigilance, slow withdrawal of drug from market etc. Hence toiling efforts have been made and should be made in investigating lacunas in national as well as international systems that encourage launch of such spurious drugs that needed withdrawals after 10-20 years of public use. This manuscript intends to collect and present data on tragic clinical trials, highlight the tragedies that occurred during the dark era of clinical trials and enumerate various corrective actions taken in response to the lessons learnt during those clinical trials.

Case Reports in the Era of Clinical Trials

Once upon a time, case reports were the primary content of scholarly medical journals. Case reports are still common but have come to be viewed more often than not as anecdotes rather than evidence. And even though David Sackett referred to the important link between clinical expertise and external evidence,1 the “gold standard” today is the randomized controlled clinical trial. Why is this?

Clinical trials in the new millennium.

Since the introduction of the randomized clinical trial (RCT) over 50 years ago, this method has become the corner stone for evaluating new pharmacologic or biologic agents with many disease areas benefiting. There are numerous examples demonstrating beneficial interventions as well as others either not beneficial or harmful. Statistical methodology for clinical trials has grown rapidly. Advances in information technology for data collection have allowed trials to be conducted around the world. Academia, industry and government have worked in partnership to conduct RCTs. Despite these many RCT achievements, the most interesting and challenging era of clinical trials lies ahead of us. With the human genome now sequenced, we face a new set of challenges to transform vast amounts of data into useful information. The post-genomics era will better identify the disease mechanism and thus help design better treatments, and be more selective in screening patients, yielding more efficient clinical trials. For some areas of medicine, such as medical devices, standards of acceptance and regulatory approval are changing. Other areas, such as medical procedures and alternative medicines, are generally not well evaluated and could benefit greatly from a wider use of RCT methodology. As the ICH guidelines facilitate and encourage international clinical trials, the scientific and ethical dimension of conducting trials in Third World countries are raised. For example, Western society's best standard of care may not be available or affordable to these countries as the control Western investigators should not exploit patients in the Third World. Those and many other challenges face us in the decade ahead. It is truly an exciting time with new opportunities for the RCT to contribute to medicine and health care or prevention.

DICTIONARY FOR CLINICAL TRIALS.

Neurology, traditionally a specialty without any effective treatments, has, in the past decade, entered the era of clinical trials and evidence-based medicine with a bang. A plethora of randomized controlled trials have evaluated treatments for stroke, epilepsy, multiple sclerosis, movement disorders, neuropathies and beyond; the list covers the whole of Clinical Neurology. Neurologists need to know about clinical trials, but as the author explains in the introduction, clinical trials have a language of their own. For the uninitiated, this dictionary will be a useful starting point in learning that language. …

Acute stroke therapy at the millennium: consummating the marriage between the laboratory and bedside. The Feinberg lecture.

Those of us in the stroke field have a big job ahead of us. When I started attending this meeting 20 years ago, most of the papers related to acute stroke therapy were laboratory related. Now, of course, we are in the era of clinical trials. But in designing clinical trials, we cannot forget the lessons that need to be learned from laboratory research. And it’s the job of the stroke neurologist to marry these 2 together, and that’s the main focus of what I’d like to talk about in the next few minutes. I’d like to make 4 key points. First, that stroke therapy is difficult. It’s a complex disease, and nobody said it would be easy. There are not going to be any magic bullets for stroke patients. Second, the most critical but ignored lesson from the laboratory is the importance of time. Third, it’s critical to change the role of neurologists in taking care of stroke patients, particularly because of the importance of time. Finally, I’d like to make a few comments about the direction of future stroke research. The bad news for acute stroke therapy is that as far as translating what we’ve done in the laboratory to clinical reality, stroke has been and always will be difficult to treat. We should expect small advances and many failures, and for every 1 positive clinical trial, we will probably have many negative ones; that’s just the nature of stroke disease. But substantial attenuation of damage is possible. I will try to show how the hopes of the laboratory have often been dashed by the reality of translation to human stroke by using an autobiographical approach. The basic principle that acute stroke is a treatable disease was demonstrated to me when I was a fellow at Massachusetts General …