A patient survey indicates quality of life and progression-free survival as equally important outcome measures in multiple myeloma clinical trials.
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ABSTRACT:
SUBMITTER: Fleischer A
PROVIDER: S-EPMC10587328 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:Measurement of overall survival (OS) remains the gold standard for interpreting the impact of new therapies for multiple myeloma in phase 3 trials. However, as outcomes have improved, it is increasingly challenging to use OS as the primary endpoint if timely approval of novel agents is to be ensured to enable maximum benefit for patients. Surrogate endpoints of OS, such as progression-free survival (PFS) and response to treatment, have contributed to approval decisions by the Food and Drug Administration (FDA) and European Medicines Agency as endpoints demonstrating clinical benefit, and the FDA has recently supported the use of minimal residual disease (MRD) as an accelerated approval endpoint in multiple myeloma. This review aims to address situations in which the use of PFS as a surrogate endpoint warrants careful interpretation especially for specific subgroups of patients and considers ways to ensure that studies can be designed to account for possible discordance between PFS and OS. The utility of subgroup analyses, including the potential for those not pre-specified, to identify target populations for new agents is also discussed.
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Project description:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an average survival of 3-5 years. While therapies for ALS remain limited, basic and translational ALS research has been host to numerous influential discoveries in recent years. These discoveries have led to a large pipeline of potential therapies that await testing in clinical trials. Until recently, ALS clinical trials have relied on a limited cadre of 'traditional' outcome measures, including survival and measures of function. These measures have proven useful, although imperfect, in Phase III ALS trials. However, their utility in early-phase ALS trials is limited. For these early trials, outcome measures focused on target engagement or biological pathway analysis might improve trial outcomes and better support the drug development process.
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Project description:Objective:We sought to (1) identify the outcome measures currently used across stroke arm rehabilitation randomized trials, (2) identify and compare outcomes important to stroke survivors, carers and clinicians and (3) describe where existing research outcome measures capture outcomes that matter the most to stroke survivors, carers and clinicians and where there may be discrepancies.Methods:First, we systematically identified and extracted data on outcome measures used in trials within a Cochrane overview of arm rehabilitation interventions. Second, we conducted 16 focus groups with stroke survivors, carers and clinicians using nominal group technique, supplemented with eight semi-structured interviews, to identify these stakeholders' most important outcomes following post-stroke arm impairment. Finally, we described the constructs of each outcome measure and indicated where stakeholders' important outcomes were captured by each measure.Results:We extracted 144 outcome measures from 243 post-stroke arm rehabilitation trials. The Fugl-Meyer Assessment Upper Extremity section (used in 79/243 trials; 33%), Action Research Arm Test (56/243; 23%), and modified Ashworth Scale (53/243; 22%) were most frequently used. Stroke survivors ( n = 43), carers ( n = 10) and clinicians ( n = 58) identified 66 unique, important outcomes related to arm impairment following stroke. Between one and three outcomes considered important by the stakeholders were captured by the three most commonly used assessments in research.Conclusion:Post-stroke arm rehabilitation research would benefit from a reduction in the number of outcome measures currently used, and better alignment between what is measured and what is important to stroke survivors, carers and clinicians.
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Project description:Imaging markers that are reliable, reproducible and sensitive to neurodegenerative changes in progressive multiple sclerosis (MS) can enhance the development of new medications with a neuroprotective mode-of-action. Accordingly, in recent years, a considerable number of imaging biomarkers have been included in phase 2 and 3 clinical trials in primary and secondary progressive MS. Brain lesion count and volume are markers of inflammation and demyelination and are important outcomes even in progressive MS trials. Brain and, more recently, spinal cord atrophy are gaining relevance, considering their strong association with disability accrual; ongoing improvements in analysis methods will enhance their applicability in clinical trials, especially for cord atrophy. Advanced magnetic resonance imaging (MRI) techniques (e.g. magnetization transfer ratio (MTR), diffusion tensor imaging (DTI), spectroscopy) have been included in few trials so far and hold promise for the future, as they can reflect specific pathological changes targeted by neuroprotective treatments. Positron emission tomography (PET) and optical coherence tomography have yet to be included. Applications, limitations and future perspectives of these techniques in clinical trials in progressive MS are discussed, with emphasis on measurement sensitivity, reliability and sample size calculation.
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Project description:Facioscapulohumeral muscular dystrophy (FSHD) is a debilitating muscular dystrophy with a variable age of onset, severity, and progression. While there is still no cure for this disease, progress towards FSHD therapies has accelerated since the underlying mechanism of epigenetic derepression of the double homeobox 4 (DUX4) gene leading to skeletal muscle toxicity was identified. This has facilitated the rapid development of novel therapies to target DUX4 expression and downstream dysregulation that cause muscle degeneration. These discoveries and pre-clinical translational studies have opened new avenues for therapies that await evaluation in clinical trials. As the field anticipates more FSHD trials, the need has grown for more reliable and quantifiable outcome measures of muscle function, both for early phase and phase II and III trials. Advanced tools that facilitate longitudinal clinical assessment will greatly improve the potential of trials to identify therapeutics that successfully ameliorate disease progression or permit muscle functional recovery. Here, we discuss current and emerging FSHD outcome measures and the challenges that investigators may experience in applying such measures to FSHD clinical trial design and implementation.
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Project description:We measured immunosuppression at myeloma diagnosis and assessed the impact on survival in 5826 UK myeloma trial patients. Polyclonal immunoglobulin levels were below normal in 85% of patients and above normal in only 0.4% of cases for IgA, 0.2% for IgM and no cases for IgG. Immunoparesis had a greater impact in recent trials: median overall survival (OS) was up to 3 years longer for patients without immunoparesis compared to the old trials, less than 1 year longer. Median progression-free survival (PFS) was 39%, 36% and 57% longer for patients with normal IgG, IgA and IgM levels, respectively. The depth of IgM suppression, but not the depth of IgG or IgA suppression, was prognostic for survival: the most severely suppressed IgM tertile of patients OS was 0.9 years shorter than those in the top tertile, and 2.6 years shorter than OS of those with normal IgM levels (p = .007). The degree of suppression of polyclonal IgM levels below normal was associated with worse PFS (p = .0002). Infection does not appear to be the main mechanism through which immunoparesis affects survival. We hypothesise that IgM immunoparesis impacts through a combination of being associated with more aggressive disease and reduced immune surveillance against relapse.
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Project description:One of the most promising approaches to delay, prevent or reverse disability progression in multiple sclerosis (MS) is to enhance endogenous remyelination and limit axonal degeneration. In clinical trials of remyelinating drugs, there is a need for reliable, sensitive and clinically relevant outcome measures. The visual pathway, which is frequently affected by MS, provides a unique model system to evaluate remyelination of acute and chronic MS lesions in vivo and non-invasively. In this review, we discuss the different measures that have been used and scrutinise visual outcome measure selection in current and future remyelination trials.
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Project description:ObjectiveA gluten-free diet is the only treatment option of coeliac disease, but recently an increasing number of trials have begun to explore alternative treatment strategies. We aimed to review the literature on coeliac disease therapeutic trials and issue recommendations for outcome measures.DesignBased on a literature review of 10 062 references, we (17 researchers and 2 patient representatives from 10 countries) reviewed the use and suitability of both clinical and non-clinical outcome measures. We then made expert-based recommendations for use of these outcomes in coeliac disease trials and identified areas where research is needed.ResultsWe comment on the use of histology, serology, clinical outcome assessment (including patient-reported outcomes), quality of life and immunological tools including gluten immunogenic peptides for trials in coeliac disease.ConclusionCareful evaluation and reporting of outcome measures will increase transparency and comparability of coeliac disease therapeutic trials, and will benefit patients, healthcare and the pharmaceutical industry.
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Project description:Background/objectivesAccurate estimates of clinically important difference (CID) are required for interpreting the clinical importance of treatments to improve physical function, but CID estimates vary in different disease populations. We determined the CID for two common measures of walking ability in mobility-limited older men.DesignLongitudinal, multisite placebo-controlled trial.Setting/participantsMen enrolled in the Testosterone Trials who had self-reported mobility limitation and gait speed less than 1.2 m/second (n = 429). Testosterone- and placebo-allocated participants were combined for this study.ResultsMean changes from baseline, adjusting for time-in-intervention and site, were 29.6, 13.2, 12.5, -2.4, and -32.6 m for 6MWD, and 15.4, 7.2, 2.1, -3.4, and -7.2 for PF10 in men who reported their mobility was "very/much better," "little better," "no change," "little worse," or "much worse," respectively. CID estimates using regression, ROC, and eCDF varied from 5.0-29.6 m for 6MWD, and 5.0-15.2 points for PF10.ConclusionCID estimates vary by the population studied and by the method and precision of measurement. Increases of 16 to 30 m for 6MWD and 5 to 15 points for PF10 over 12 months appear to be clinically meaningful in mobility-limited, older hypogonadal men. These CID estimates may be useful in the design of efficacy trials of therapies to improve physical function.
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Project description: Not available
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