Age at onset in genetic prion disease and the design of preventive clinical trials

ObjectiveTo determine whether preventive trials in genetic prion disease could be designed to follow presymptomatic mutation carriers to onset of disease.MethodsWe assembled age at onset or death data from 1,094 individuals with high penetrance mutations in the prion protein gene (PRNP) in order to generate survival and hazard curves and test for genetic modifiers of age at onset. We used formulae and simulations to estimate statistical power for clinical trials.ResultsGenetic prion disease age at onset varies over several decades for the most common mutations and neither sex, parent's age at onset, nor PRNP codon 129 genotype provided additional explanatory power to stratify trials. Randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials.ConclusionThe characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a postmarketing study could provide opportunities for subsequent determination of clinical benefit.

Download Full-text

Age of onset in genetic prion disease and the design of preventive clinical trials

10.1101/401406 ◽

2018 ◽

Cited By ~ 2

Author(s):

Eric Vallabh Minikel ◽

Sonia M Vallabh ◽

Margaret C Orseth ◽

Jean-Philippe Brandel ◽

Stéphane Haïk ◽

...

Keyword(s):

Clinical Trials ◽

Prion Disease ◽

Clinical Benefit ◽

Statistical Power ◽

Age Of Onset ◽

Traditional Approach ◽

Trial Duration ◽

Quantitative Evidence ◽

Post Marketing ◽

Prohibitive Cost

AbstractRegulatory agencies worldwide have adopted programs to facilitate drug development for diseases where the traditional approach of a randomized trial with a clinical endpoint is expected to be prohibitively lengthy or difficult. Here we provide quantitative evidence that this criterion is met for the prevention of genetic prion disease. We assemble age of onset or death data fromN=1,094 individuals with high penetrance mutations in the prion protein gene (PRNP), generate survival and hazard curves, and estimate statistical power for clinical trials. We show that, due to dramatic and unexplained variability in age of onset, randomized preventive trials would require hundreds or thousands of at-risk individuals in order to be statistically powered for an endpoint of clinical onset, posing prohibitive cost and delay and likely exceeding the number of individuals available for such trials. Instead, the characterization of biomarkers suitable to serve as surrogate endpoints will be essential for the prevention of genetic prion disease. Biomarker-based trials may require post-marketing studies to confirm clinical benefit. Parameters such as longer trial duration, increased enrollment, and the use of historical controls in a post-marketing study could provide opportunities for subsequent determination of clinical benefit.

Download Full-text

Which Outcome Indices Would Clinicians Like to See in Schizophrenia Clinical Trials?

European Psychiatry ◽

10.1016/s0924-9338(11)73907-4 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 2204-2204

Author(s):

S. Galderisi

Keyword(s):

Clinical Trials ◽

Clinical Practice ◽

Outcome Measures ◽

Statistical Power ◽

Outcome Measurement ◽

Trial Duration ◽

Measurement Tools ◽

Remission Criteria ◽

Research Findings ◽

Study Designs

Outcome measurement tools were almost exclusively used, so far, in research studies, while in routine clinical practice gross descriptive evaluation was generally provided. Discrepancies among studies and among stakeholders as to the effectiveness of one or the other treatment, study designs based on strict inclusion and exclusion criteria unlikely to generalize to clinical practice, the choice of outcome measures not always clinically meaningful, difficulties in the interpretation of clinical trials results and the relatively short trial duration have contributed to clinicians’ skeptical attitude toward clinical trials findings. Researchers designing future clinical trials are confronted with the need of providing clinically meaningful outcome measures, without undermining the statistical power of the study. However, integrative measures, such as "time to discontinuation for any reason", thought to convey information about efficacy, tolerability and safety, can be influenced by several nonspecific variables likely to vary from site to site and from doctor to doctor. Simple and global measurements, such as CGI-SCH, while preferred by many clinicians, might not capture the non unitary nature of the schizophrenia outcome constructs. Remission criteria are still limited to symptoms and clinicians would certainly like to see criteria for functional remission implemented as well. Clinical trials based on simple designs and on more comprehensive outcome measures will probably contribute to reduce the gap between research findings and clinical practice.

Download Full-text

Efficient interspecies transmission of synthetic prions

PLoS Pathogens ◽

10.1371/journal.ppat.1009765 ◽

2021 ◽

Vol 17 (7) ◽

pp. e1009765

Author(s):

Alyssa J. Block ◽

Ronald A. Shikiya ◽

Thomas E. Eckland ◽

Anthony E. Kincaid ◽

Ryan W. Walters ◽

...

Keyword(s):

Prion Disease ◽

Protein Misfolding ◽

Conformational Stability ◽

Cellular Protein ◽

Interspecies Transmission ◽

Species Barrier ◽

Single Strain ◽

Clinical Onset ◽

Bona Fide

Prions are comprised solely of PrPSc, the misfolded self-propagating conformation of the cellular protein, PrPC. Synthetic prions are generated in vitro from minimal components and cause bona fide prion disease in animals. It is unknown, however, if synthetic prions can cross the species barrier following interspecies transmission. To investigate this, we inoculated Syrian hamsters with murine synthetic prions. We found that all the animals inoculated with murine synthetic prions developed prion disease characterized by a striking uniformity of clinical onset and signs of disease. Serial intraspecies transmission resulted in a rapid adaptation to hamsters. During the adaptation process, PrPSc electrophoretic migration, glycoform ratios, conformational stability and biological activity as measured by protein misfolding cyclic amplification remained constant. Interestingly, the strain that emerged shares a strikingly similar transmission history, incubation period, clinical course of disease, pathology and biochemical and biological features of PrPSc with 139H, a hamster adapted form of the murine strain 139A. Combined, these data suggest that murine synthetic prions are comprised of bona fide PrPSc with 139A-like strain properties that efficiently crosses the species barrier and rapidly adapts to hamsters resulting in the emergence of a single strain. The efficiency and specificity of interspecies transmission of murine synthetic prions to hamsters, with relevance to brain derived prions, could be a useful model for identification of structure function relationships between PrPSc and PrPC from different species.

Download Full-text

Modeling Clinical Trial Attrition Using Machine Intelligence: A driver analytics case study using 1,325 trials representing one million patients

10.1101/2021.11.12.21266277 ◽

2021 ◽

Author(s):

Emmette Hutchison ◽

Sreenath Nampally ◽

Imran Khan Neelufer ◽

Youyi Zhang ◽

Jim Weatherall ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Machine Intelligence ◽

Duration Of Treatment ◽

Trial Duration ◽

Major Barrier ◽

Clinical Phase ◽

Successful Execution ◽

Patient Attrition ◽

Data Driven Approach

The amount of time and resources invested in bringing novel therapeutics to market has increased year over year with fewer successful treatments reaching patients. In the lifecycle of drug development, the clinical phase is a major contributor to this decreasing efficiency in the development of clinical trials. One major barrier to the successful execution of a randomized control trial (RCT) is the attrition of patients who no longer participate in a trial either following enrollment or randomization. To address this problem, we have assembled a unique dataset by integrating multiple public databases including ClinicalTrials.gov and Aggregate Analysis of ClincalTrials.gov (AACT) to assemble a trial sponsor-independent dataset. This data spans 20 years of clinical trials and over 1 million patients (3,175 cohorts consisting of 1,020,085 patients and 79 curated features) in the respiratory domain and enabled a data-driven approach to identify top features influencing patient attrition in a trial. Top Features included Duration of Trial, Duration of Treatment, Indication, and Number of Adverse Events. We evaluated multiple machine learning models and found the best performance on the Test Set with Random Forest (Test subset: n=637 cohorts; RMSE 6.64). We envisage that our work will enable clinical trial sponsors to optimize trial run time by better anticipating and correcting for potential patient attrition using patient-centric strategies to improve patient engagement, thus enabling new therapies to be delivered to patients more quickly.

Download Full-text

Statistical power of clinical trials increased while effect size remained stable: an empirical analysis of 136,212 clinical trials between 1975 and 2014

Journal of Clinical Epidemiology ◽

10.1016/j.jclinepi.2018.06.014 ◽

2018 ◽

Vol 102 ◽

pp. 123-128 ◽

Cited By ~ 12

Author(s):

Herm J. Lamberink ◽

Willem M. Otte ◽

Michel R.T. Sinke ◽

Daniël Lakens ◽

Paul P. Glasziou ◽

...

Keyword(s):

Clinical Trials ◽

Empirical Analysis ◽

Effect Size ◽

Statistical Power

Download Full-text

Friedreich and dominant ataxias: quantitative differences in cerebellar dysfunction measurements

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2017-316964 ◽

2017 ◽

Vol 89 (6) ◽

pp. 559-565 ◽

Cited By ~ 9

Author(s):

Audrey Tanguy Melac ◽

Caterina Mariotti ◽

Antoine Filipovic Pierucci ◽

Paola Giunti ◽

Javier Arpa ◽

...

Keyword(s):

Clinical Trials ◽

Outcome Measures ◽

Spinocerebellar Ataxia ◽

Disease Duration ◽

Age At Onset ◽

Cerebellar Dysfunction ◽

Quantitative Measurements ◽

Registration Number ◽

Cerebellar Ataxias ◽

Late Stages

BackgroundSensitive outcome measures for clinical trials on cerebellar ataxias are lacking. Most cerebellar ataxias progress very slowly and quantitative measurements are required to evaluate cerebellar dysfunction.MethodsWe evaluated two scales for rating cerebellar ataxias: the Composite Cerebellar Functional Severity (CCFS) Scale and Scale for the Assessment and Rating of Ataxia (SARA), in patients with spinocerebellar ataxia (SCA) and controls. We evaluated these scales for different diseases and investigated the factors governing the scores obtained. All patients were recruited prospectively.ResultsThere were 383 patients with Friedreich’s ataxia (FRDA), 205 patients with SCA and 168 controls. In FRDA, 31% of the variance of cerebellar signs with the CCFS and 41% of that with SARA were explained by disease duration, age at onset and the shorter abnormal repeat in the FXN gene. Increases in CCFS and SARA scores per year were lower for FRDA than for SCA (CCFS index: 0.123±0.123 per year vs 0.163±0.179, P<0.001; SARA index: 1.5±1.2 vs 1.7±1.7, P<0.001), indicating slower cerebellar dysfunction indexes for FRDA than for SCA. Patients with SCA2 had higher CCFS scores than patients with SCA1 and SCA3, but similar SARA scores.ConclusionsCerebellar dysfunction, as measured with the CCFS and SARA scales, was more severe in FRDA than in patients with SCA, but with lower progression indexes, within the limits of these types of indexes. Ceiling effects may occur at late stages, for both scales. The CCFS scale is rater-independent and could be used in a multicentre context, as it is simple, rapid and fully automated.Trial registration numberClinicalTrials.gov: NCT02069509.

Download Full-text

The continuous heart failure spectrum: moving beyond an ejection fraction classification

European Heart Journal ◽

10.1093/eurheartj/ehz158 ◽

2019 ◽

Vol 40 (26) ◽

pp. 2155-2163 ◽

Cited By ~ 57

Author(s):

Filippos Triposkiadis ◽

Javed Butler ◽

Francois M Abboud ◽

Paul W Armstrong ◽

Stamatis Adamopoulos ◽

...

Keyword(s):

Heart Failure ◽

Clinical Trials ◽

Ejection Fraction ◽

Statistical Power ◽

Structural Changes ◽

Randomized Clinical Trials ◽

New Technologies ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction

Abstract Randomized clinical trials initially used heart failure (HF) patients with low left ventricular ejection fraction (LVEF) to select study populations with high risk to enhance statistical power. However, this use of LVEF in clinical trials has led to oversimplification of the scientific view of a complex syndrome. Descriptive terms such as ‘HFrEF’ (HF with reduced LVEF), ‘HFpEF’ (HF with preserved LVEF), and more recently ‘HFmrEF’ (HF with mid-range LVEF), assigned on arbitrary LVEF cut-off points, have gradually arisen as separate diseases, implying distinct pathophysiologies. In this article, based on pathophysiological reasoning, we challenge the paradigm of classifying HF according to LVEF. Instead, we propose that HF is a heterogeneous syndrome in which disease progression is associated with a dynamic evolution of functional and structural changes leading to unique disease trajectories creating a spectrum of phenotypes with overlapping and distinct characteristics. Moreover, we argue that by recognizing the spectral nature of the disease a novel stratification will arise from new technologies and scientific insights that will shape the design of future trials based on deeper understanding beyond the LVEF construct alone.

Download Full-text

Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease

Pathogens ◽

10.3390/pathogens9060482 ◽

2020 ◽

Vol 9 (6) ◽

pp. 482

Author(s):

Simote Foliaki ◽

Bradley Groveman ◽

Jue Yuan ◽

Ryan Walters ◽

Shulin Zhang ◽

...

Keyword(s):

Prion Protein ◽

Prion Disease ◽

Neurological Disorders ◽

Prion Diseases ◽

Three Dimensional ◽

Protein Isoforms ◽

Genetic Modifiers ◽

Neuronal Tissue ◽

Prion Infection ◽

E200k Mutation

Cerebral organoids (COs) are a self-organizing three-dimensional brain tissue mimicking the human cerebral cortex. COs are a promising new system for modelling pathological features of neurological disorders, including prion diseases. COs expressing normal prion protein (PrPC) are susceptible to prion infection when exposed to the disease isoforms of PrP (PrPD). This causes the COs to develop aspects of prion disease pathology considered hallmarks of disease, including the production of detergent-insoluble, protease-resistant misfolded PrPD species capable of seeding the production of more misfolded species. To determine whether COs can model aspects of familial prion diseases, we produced COs from donor fibroblasts carrying the E200K mutation, the most common cause of human familial prion disease. The mature E200K COs were assessed for the hallmarks of prion disease. We found that up to 12 months post-differentiation, E200K COs harbored no PrPD as confirmed by the absence of detergent-insoluble, protease-resistant, and seeding-active PrP species. Our results suggest that the presence of the E200K mutation within the prion gene is insufficient to cause disease in neuronal tissue. Therefore, other factors, such as further genetic modifiers or aging processes, may influence the onset of misfolding.

Download Full-text

Unequal Randomisation Can Improve the Economic Efficiency of Clinical Trials

Journal of Health Services Research & Policy ◽

10.1177/135581969700200205 ◽

1997 ◽

Vol 2 (2) ◽

pp. 81-85 ◽

Cited By ~ 16

Author(s):

David Torgerson ◽

Marion Campbell

Keyword(s):

Clinical Trials ◽

Sample Size ◽

Statistical Power ◽

Cost Effective ◽

Total Sample ◽

Cost Ratio ◽

Treatment Groups ◽

Total Sample Size ◽

Effectiveness Analysis ◽

Research Resources

Objectives: In the majority of clinical trials patients are randomised equally between treatment groups. This approach maximises statistical power for a given total sample size. The objectives of this paper were to determine if, when research costs between treatments differ, it is more economically efficient to randomise additional patients to the cheaper treatment, and how the optimum randomisation ratio can be estimated. Methods: Estimation of the most economically efficient randomisation ratio for four hypothetical clinical trials using cost-effectiveness analysis. Results: When research costs differ between treatments, and there is no constraint on total sample size, it is always more cost-effective to randomise more patients to the cheaper treatment. For example, a cost ratio between the lesser and more expensive treatment of ten, results in a randomisation ratio of 3.2:1. Conclusions: Unequal randomisation ratios should be more widely used as this will achieve optimum statistical power for the lowest expenditure of research resources.

Download Full-text

EM2: THE IMPACT OF HOSPITAL COSTING METHODS ON STATISTICAL POWER IN MULTINATIONAL CLINICAL TRIALS

Value in Health ◽

10.1046/j.1524-4733.2001.40201-2.x ◽

2001 ◽

Vol 4 (2) ◽

pp. 47

Author(s):

SD Reed ◽

JY Friedman ◽

JH Malenbaum ◽

A Gnanasakthy ◽

KA Schulman

Keyword(s):

Clinical Trials ◽

Statistical Power ◽

The Impact

Download Full-text