Recommendations For Future Clinical Trials Research Articles

Past Trends and Future Directions of Cardiac Regenerative Medicine - A Systematic Analysis of Clinical Trial Registries.

Cell therapy, gene therapy, and tissue engineering have been explored as potential strategies to repair or regenerate damaged cardiac tissue. Despite the presence of encouraging preclinical data, clinical trials of regenerative cardiac therapies have yielded mixed results. Our study aimed to investigate the fate of all registered clinical trials within regenerative cardiac medicine, with the purpose of exploring the potential role of publication bias (or trial-completion bias), how published and unpublished research affects the field, and to draw lessons and recommendations for future clinical trials. In this analysis, we show that only a third of all registered trials has yielded results and that a significant number of trials are not completed. Furthermore, we identified significant heterogeneity in study design, study phase, funding, specific therapies used, primary outcome measures and methods of outcome assessment. These observations might hinder the successful translation of cardiac regenerative therapies into clinical practice.

Defining clinically useful biomarkers of immune checkpoint inhibitors in solid tumours.

Although more than a decade has passed since the approval of immune checkpoint inhibitors (ICIs) for the treatment of melanoma and non-small-cell lung, breast and gastrointestinal cancers, many patients still show limited response. US Food and Drug Administration (FDA)-approved biomarkers include programmed cell death 1 ligand 1 (PDL1) expression, microsatellite status (that is, microsatellite instability-high (MSI-H)) and tumour mutational burden (TMB), but these have limited utility and/or lack standardized testing approaches for pan-cancer applications. Tissue-based analytes (such as tumour gene signatures, tumour antigen presentation or tumour microenvironment profiles) show a correlation with immune response, but equally, these demonstrate limited efficacy, as they represent a single time point and a single spatial assessment. Patient heterogeneity as well as inter- and intra-tumoural differences across different tissue sites and time points represent substantial challenges for static biomarkers. However, dynamic biomarkers such as longitudinal biopsies or novel, less-invasive markers such as blood-based biomarkers, radiomics and the gut microbiome show increasing potential for the dynamic identification of ICI response, and patient-tailored predictors identified through neoadjuvant trials or novel ex vivo tumour models can help to personalize treatment. In this Perspective, we critically assess the multiple new static, dynamic and patient-specific biomarkers, highlight the newest consortia and trial efforts, and provide recommendations for future clinical trials to make meaningful steps forwards in the field.

Lessons Learned From Clinical Studies in Centronuclear Myopathies: The Patient Perspective—A Qualitative Study

BackgroundSince 2014, several clinical studies focusing on centronuclear myopathies have been conducted, including a prospective natural history study, a gene transfer clinical trial and a clinical trial using an antisense oligonucleotide. Dedicated patient organizations have played an important role in this process. The experience of members of these organizations, either as a study participant, parent or as a patient organization member communicating with the sponsors are potentially very informative for future trial design. MethodsWe investigated the burden of and the lessons learned from the first natural history studies and clinical trials from a patient perspective using a qualitative approach. We arranged 4 focus groups with a total of 37 participants from 3 large international patient organizations: ZNM-ZusammenStark!, the Myotubular Trust, and the MTM-CNM Family Connection. 4 themes, based on a systematic literature search were discussed: Expectations and preparation, Clinical study participation, Communication and Recommendations for future clinical trials. The focus group recordings were transcribed, anonymized, and uploaded to Atlas-ti version 8.1 software. The data were analyzed using a thematic content analysis. ResultsOverall, participants were realistic in their expectations, hoping for small improvements of function and quality of life. The realization that trial participation does not equate to a treatment was challenging. Participating in a clinical study had a huge impact on many aspects of daily life, both for patients and their immediate families. First-hand insights into the burden of the design and its possible effect on performance were provided, resulting in numerous compelling recommendations for future clinical studies. Furthermore, participants stressed the importance of clear communication, which was considered to be especially vital in cases of severe adverse events. Finally, while patients were understanding of the importance of adhering to the regulations of good clinical practice, they indicated that they would strongly appreciate a greater understanding and/or acknowledgment of the patient perspective and a reflection of this perspective in future clinical trial design. ConclusionThe acknowledgment and inclusion of patients’ perspectives and efficient and effective communication is expected to improve patient recruitment and retention in future clinical studies, as well as more accurate assessment of the patient performance related to suitable planning of the study visits.

Assessing Motor Function in Frail Older Adults in Their Home Settings: Challenges, Strategies and Recommendations.

Assessing motor competence is essential for evaluating the effectiveness of physical activity interventions that aim to maintain or improve older adults' function. However, assessing motor competence in older adults who have difficulties walking or standing is challenging, because few instruments or guidelines are appropriate for these frail older adults. This article aims to describe challenges in evaluating motor function among frail older adults, discuss strategies for adapting motor function assessments to their home settings, and provide recommendations for future clinical trials so that older adults with ambulatory difficulties can benefit from motor function assessment and physical activity programs. Data came from the baseline assessment of 116 participants of an ongoing clinical trial, "Promoting Seniors' Health with Home Care Aides (Pro-Home)". Our results demonstrated that the Pro-Home study involved participants who would be typically excluded from clinical trials and that the two instruments selected or developed for Pro-Home (Short Physical Performance Battery, Pro-Home Ankle Range of Motion Measure) captured a wide range of lower extremity motor competence with no or few missing data. Recommendations for future studies include knowing the target population thoroughly, developing trust and rapport with all parties involved, and continuously collaborating with interviewers who conduct assessments.

15716 The high rate of placebo response in hidradenitis suppurativa clinical trials: Recommendations for future clinical trials

The authors recently published a systematic review showing a robust placebo response in randomized clinical trials (RCTs) for hidradenitis suppurativa (HS), especially for physical signs. Three additional international/US-based RCTs for moderate-severe HS patients have been reported that did not meet the primary end point and demonstrated high placebo responses (n = 66-179). Four active doses of IFX-1 (IV anti–human complement factor C5a monoclonal antibody; InflaRx) were compared with placebo. IFX-1 treatment achieved a maximum HS Clinical Response (HiSCR) rate of 51.5% while placebo resulted in HiSCR of 47.1%. An RCT investigated MEDI8968 (subcutaneous interleukin-1 receptor 1 inhibitor, AstraZeneca). 23.6% of participants were responders in the active arm (PGA score of 0, 1 or 2 at week 12) compared with 18.5% of those receiving placebo. The study was terminated early. The third RCT compared CJM112 (subcutaneous anti–IL-17A monoclonal antibody; Novartis) versus placebo. Of those receiving active treatment, 32% were responders (decrease in HS-PGA of at least 2 points), while 12.5% of those receiving placebo met this definition. In order to accommodate the large and variable placebo response in HS, the following should be considered: recruit HS patients from well established HS practices, stratify recruitment and randomization across all spectrums of disease activity, employ a trial duration which will account for the natural history of the disease, agree upon a verified set of primary and secondary outcomes; and employ diagnostic imaging techniques to mitigate subjectivity in assessing outcomes. Furthermore, publishing negative outcomes should be encouraged in order to learn from all HS RCTs.

Mindfulness Training, Implicit Bias, and Force Response Decision-making.

The goal of this study was to assess the preliminary efficacy of a Mindfulness-Based Training (Mindfulness-based Resilience Training; MBRT) in improving weapon identification among Law Enforcement Officers (LEOs). Participants (N = 61) were randomly assigned to either MBRT or a no-intervention control group (NIC). A self-report questionnaire assessing mindfulness and a computerized measure assessing implicit stereotype reliance were administered at baseline, post-training, and three months following intervention completion. We also collected information about meditation practice outside of the training for LEOs in the MBRT group. Inferential analyses yielded improvements in mindfulness in the MBRT group compared to NIC. Analyses did not provide evidence for implicit stereotype reliance at baseline and therefore did not yield a significant impact of MBRT versus NIC on implicit stereotype reliance, ps > .05; however, participants across both conditions exerted more control when responding to Black male targets compared to White male targets, F(1,74) = 3.98, p = .05, 95% CI [-.05, -.01], d = .36. Our results do not provide evidence for the impact of MBRT on weapon identification, but do suggest that LEOs exerted more effort when responding to images of Black males compared to White males. We discuss recommendations for future clinical trials assessing implicit stereotype reliance, viz., that researchers utilize measures more sensitive to a wider range of LEO samples and with higher ecological validity, and we discuss potential reasons why our results do not align with past research.

Clinical Development of Targeted Fragile X Syndrome Treatments: An Industry Perspective.

Fragile X syndrome (FXS) is the leading known cause of inherited intellectual disability and autism spectrum disorder. It is caused by a mutation of the fragile X mental retardation 1 (FMR1) gene, resulting in a deficit of fragile X mental retardation protein (FMRP). The clinical presentation of FXS is variable, and is typically associated with developmental delays, intellectual disability, a wide range of behavioral issues, and certain identifying physical features. Over the past 25 years, researchers have worked to understand the complex relationship between FMRP deficiency and the symptoms of FXS and, in the process, have identified several potential targeted therapeutics, some of which have been tested in clinical trials. Whereas most of the basic research to date has been led by experts at academic institutions, the pharmaceutical industry is becoming increasingly involved with not only the scientific community, but also with patient advocacy organizations, as more promising pharmacological agents are moving into the clinical stages of development. The objective of this review is to provide an industry perspective on the ongoing development of mechanism-based treatments for FXS, including identification of challenges and recommendations for future clinical trials.

New Insights about How to Make an Intervention in Children and Adolescents with Metabolic Syndrome: Diet, Exercise vs. Changes in Body Composition. A Systematic Review of RCT.

Objective: To record which interventions produce the greatest variations in body composition in patients ≤19 years old with metabolic syndrome (MS). Method: search dates between 2005 and 2017 in peer reviewed journals, following the PRISMA method (Preferred Reporting Items for Systematic reviews and Meta-Analyses). The selection criteria were: diagnostic for MS or at least a criterion for diagnosis; randomized clinical trials, ≤19 years of age; intervention programs that use diet and/or exercise as a tool (interventions showing an interest in body composition). Results: 1781 clinical trials were identified under these criteria but only 0.51% were included. The most frequent characteristics of the selected clinical trials were that they used multidisciplinary interventions and were carried out in America. The most utilized parameters were BMI (body mass index) in kg/m2 and BW (body weight) in kg. Conclusions: Most of the clinical trials included had been diagnosed through at least 2 diagnostic criteria for MS. Multidisciplinary interventions obtained greater changes in body composition in patients with MS. This change was especially prevalent in the combinations of dietary interventions and physical exercise. It is proposed to follow the guidelines proposed for patients who are overweight, obese, or have diabetes type 2, and extrapolate these strategies as recommendations for future clinical trials designed for patients with MS.

Dietary Supplement Comprised of β-Carotene, Vitamin C, Vitamin E, and Magnesium: Failure to Prevent Music-Induced Temporary Threshold Shift

This study examined potential prevention of music-induced temporary threshold shift (TTS) in normal-hearing participants. A dietary supplement composed of β-carotene, vitamins C and E, and magnesium was assessed using a randomized, placebo-controlled, double-blind study design. Dosing began 3 days prior to the music exposure with the final dose consumed approximately 30-min pre-exposure. Post-exposure TTS was measured, with no significant difference as a function of treatment. Distortion product otoacoustic emission amplitudes were suppressed after music exposure in both groups, with no significant difference as a function of treatment. Tinnitus was more likely to be reported by the treatment group, but there were no group differences in perceived loudness or bothersomeness. Taken together, this supplement had no effect on noise-induced changes in hearing. Recommendations for future clinical trials are discussed.

Evaluating the efficacy of therapeutic HIV vaccines through analytical treatment interruptions.

IntroductionThe development of an effective therapeutic HIV vaccine that induces immunologic control of viral replication, thereby eliminating or reducing the need for antiretroviral therapy (ART), would be of great value. Besides the obvious challenges of developing a therapeutic vaccine that would generate effective, sustained anti-HIV immunity in infected individuals is the issue of how to best assess the efficacy of vaccine candidates.DiscussionThis review discusses the various outcome measures assessed in therapeutic HIV vaccine clinical trials involving individuals receiving suppressive ART, with a particular focus on the role of analytical treatment interruption (ATI) as a way to assess the virologic control induced by an immunotherapy. This strategy is critical given that there are otherwise no readily available measures to determine the ability of a vaccine-induced immune response to effectively control HIV replication. The various outcome measures that have been used to assess vaccine efficacy in published therapeutic HIV vaccine clinical trials will also be discussed. Outcome measures have included the kinetics of viral rebound, the new viral set point and changes in the size of the viral reservoir. Clinically relevant outcomes such as the CD4 decline, the time to resume therapy or the time to meet the criterion to resume therapy, the proportion of participants who resume therapy and/or the development of clinical symptoms such as acute retroviral syndrome are also measures of vaccine efficacy.ConclusionsGiven the lack of consistency between therapeutic HIV vaccine trials in how efficacy is assessed, comparing vaccines has been difficult. It would, therefore, be beneficial to determine the most clinically relevant measure for use in future studies. Other recommendations for future clinical trials also include studying compartments in addition to blood and replacing ATIs with single-copy assays in situations in which the use of an ATI is not ideal.

Pharmacological therapies in post stroke recovery: recommendations for future clinical trials

Stroke is a leading cause of serious long-term disability in adults and is the second leading cause of death worldwide. Early reperfusion and neuroprotection techniques have been the focus of much effort with the aim of very acute treatment of the stroke. Targeting different mechanisms, pharmacological therapies have the potential to reduce disability in a large fraction of patients who survive the acute stroke. The brain's capacity to reorganize after stroke through plasticity mechanisms can be modulated by pharmacological agents. A number of therapeutic interventions are under study, including small molecules, growth factors, and monoclonal antibodies. Recently it has been shown that the SSRI fluoxetine improved motor deficit in patients with ischaemic stroke and hemiplegia which appeared to be independent of the presence of depression. In this context, it is of major importance to support innovative research in order to promote the emergence of new pharmacological treatments targeting neurological recovery after stroke, as opposed to acute de-occlusion and neuroprotection. This paper is the work of a group of 14 scientists with aim of (1) addressing key areas of the basic and clinical aspects of human brain plasticity after stroke and potential pharmacological targets for recovery, (2) asking questions about the most appropriate characteristics of clinical trials testing drugs in post stroke recovery and (3) proposing recommendations for future clinical trials.

Longitudinal FEV1 dose–response model for inhaled PF-00610355 and salmeterol in patients with chronic obstructive pulmonary disease

The objective of this work was to characterize the dose-response relationship between two inhaled long-acting beta agonists (PF-00610355 and salmeterol) and the forced expiratory volume in one second (FEV1) in order to inform dosing recommendations for future clinical trials in patients with chronic obstructive pulmonary disease (COPD). This meta-analysis of four studies included 8,513 FEV1 measurements from 690 patients with moderate COPD. A longitudinal kinetic-pharmacodynamic (K-PD) model was developed and adequately described changes in FEV1 measurements over time, including circadian patterns within a day, as well as changes in FEV1 measurements elicited from administration of PF-00610355 or salmeterol. The fine-particle dose, the amount of drug present in particles small enough for lung delivery, was used as the exposure measure for PF-00610355. Greater reversibility following administration of a short-acting beta agonist during run-in was associated with increased FEV1 response to long-acting beta agonists (through an increased maximal response, E(max)). Simulations were conducted to better understand the response to PF-00610355 relative to placebo and salmeterol. The results of the simulations show that once daily fine-particle doses of 28.1μg versus placebo have a moderate probability of providing an average improvement above 100mL at trough. The 50μg fine-particle dose, on the other hand, has a greater than 0.78 probability of achieving a 120mL improvement versus placebo at trough. From an efficacy perspective and assuming a fine-particle fraction of 25% for the Phase 3 formulation; 100 and 200μg once daily nominal doses would be of interest to investigate in future Phase 3 trials.

New Considerations in the Design of Clinical Trials for Bone Metastases.

Palliative radiotherapy (RT) is prescribed to patients with bone metastases to alleviate symptoms and improve quality of life. The lack of consistent endpoints for such trials has made cross study comparison difficult and has led to contradictory conclusions. The International Bone Metastases Consensus Working Party was established to create a standard set of endpoints and recommendations for future clinical trials. Recommendations were included regarding eligibility criteria, pain assessments, follow-up assessments, timing, as well as radiation techniques. Suggestions were also made to facilitate the ease with which different studies could be compared as well as to encourage widespread consistency in certain aspects of trial design. Investigators conducting clinical trials in bone metastases should continue to adopt these recommendations to ensure consistent guidelines based on the most recent literature.

Polyunsaturated fatty acids and epilepsy

Omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) are dietary fatty acids that are involved in a myriad of physiologic processes in the brain. There is some evidence suggesting that PUFAs-and particularly omega-3 PUFAs-may have anticonvulsant effects, both in humans and in animals. In the present review, we assess the evidence related to the antiseizure properties of the n-3 PUFAs, discuss their possible mechanism(s) of action, and make recommendations for future clinical trials. In general, the available data from cell cultures and whole animal studies support the idea that the n-3 PUFAs have antiseizure properties. Future clinical trials involving the n-3 PUFAs should involve higher doses and longer periods of administration in order to definitively assess their possible antiseizure effects.

Internet in clinical research based on a pilot experience

Computing has become an integral part of many disciplines nowadays, turning it into an evermore necessary working tool. Internet provides a fast and easy way to collect scientific data and is becoming a more and more effective and safe way to transmit data. It is also an efficient means for interaction and information sharing within a work group that provides the necessary flexibility. A pilot project was conducted replacing the traditional hardcopy version of the case report form for an electronic one (e-CRF) and with access to Internet within the Naturalistic Randomized Clinical Trial of the Effectiveness of Olanzapine and Risperidone in the Treatment of Schizophrenia. Carrying out this pilot project has given us the opportunity to determine the advantages electronic data collection (EDC) by Internet has to offer both researchers and sponsors. The results have optimized time management, since it is easier to work in real time; data quality is improved, since intermediates are eliminated, and it facilitates communication amongst the different parties involved in the project. The use of this technology requires updated Internet connections and adequate personal computers, since the possibilities offered by the computer system and high-speed connection are critical in conducting the project. Obviously, this may involve a higher initial investment, but the results have revealed to us that these start-up costs are later offset by lowering personnel costs or by decreasing the number of monitoring visits. On the basis of our experience and that of the participating investigators, certain recommendations for future clinical trials using e-CRF can be made. We will go into these recommendations in greater depth throughout this paper. In short, EDC can dramatically improve the clinical trial process, opening the door to new technologies in the world of clinical research, not only for sponsors, but also for clinicians.

Potential Strategies for Inflammatory Mediator Manipulation: Retrospect and Prospect

Sepsis syndrome and septic shock remain significant causes of morbidity and mortality. To date, clinical trials of novel agents to treat sepsis have failed to demonstrate clinical efficacy despite considerable animal data to suggest a positive therapeutic benefit. This article reviews the recent major clinical trials on sepsis and discusses the hypotheses on which these therapies are based and the critical issues associated with clinical sepsis. Recommendations for future clinical trials on sepsis are made.

Report of the workshop on clinical trials

Summary During the Third International Symposium, a leading panel of experts in the field discussed the current most prominent problems in the treatment of Hodgkin's disease to give recommendations for future clinical trials. Within the workshop on clinical trials the following issues were addressed: 1. Which diagnostic procedures are state of the art and to what extent are they able to contribute to a so-called response- adapted treatment (RAT)? 2. What is the optimal dose and volume of radiotherapy in different stages? 3. What is the value of chemotherapy in early stages and is it restricted to a certain subgroup? 3. Have we achieved as much as we can in intermediate stages in terms of response with now focusing future efforts on reducing toxicity and improving quality of live? 5. Is high-dose chemotherapy (HDCT) the answer to the challenge of improving treatment results in advanced stages? 6. What is the optimal schedule and dose of HDCT and consecutive autologous bone marrow transplantation (ABMT)?

Can second-generation versions of existing therapeutics be successful in clinical trials of sepsis?

Sepsis syndrome and septic shock remain as significant causes of morbidity and mortality. To date, clinical trials of immunotherapeutic agents have failed to establish conclusively a role for these agents despite considerable animal data to suggest a positive benefit. This article discusses the hypotheses upon which these therapies are based, the critical issues associated with clinical trials and the molecules which have been clinically tested. Recommendations for future clinical trials in sepsis are made.