scholarly journals Suggestions for improving the design of clinical trials in multiple sclerosis—results of a systematic analysis of completed phase III trials

2019 ◽  
Vol 10 (4) ◽  
pp. 425-436 ◽  
Author(s):  
Sinje Gehr ◽  
Thomas Kaiser ◽  
Reinhold Kreutz ◽  
Wolf-Dieter Ludwig ◽  
Friedemann Paul
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Patient Reported Outcomes ◽  
Progressive Multiple Sclerosis ◽  
Phase Iii ◽  
Primary Progressive Multiple Sclerosis ◽  
Systematic Overview ◽  
Patient Reported ◽  
Phase Iii Trials ◽  
Secondary Endpoints

AbstractThis manuscript reviews the primary and secondary endpoints of pivotal phase III trials with immunomodulatory drugs in multiple sclerosis (MS). Considering the limitations of previous trial designs, we propose new standards for the planning of clinical trials, taking into account latest insights into MS pathophysiology and patient-relevant aspects. Using a systematic overview of published phase III (pivotal) trials performed as part of application for drug market approval, we evaluate the following characteristics: trial duration, number of trial participants, comparators, and endpoints (primary, secondary, magnetic resonance imaging outcome, and patient-reported outcomes). From a patient perspective, the primary and secondary endpoints of clinical trials are only partially relevant. High-quality trial data pertaining to efficacy and safety that stretch beyond the time frame of pivotal trials are almost non-existent. Understanding of long-term benefits and risks of disease-modifying MS therapy is largely lacking. Concrete proposals for the trial designs of relapsing (remitting) multiple sclerosis/clinically isolated syndrome, primary progressive multiple sclerosis, and secondary progressive multiple sclerosis (e.g., study duration, mechanism of action, and choice of endpoints) are presented based on the results of the systematic overview. Given the increasing number of available immunotherapies, the therapeutic strategy in MS has shifted from a mere “relapse-prevention” approach to a personalized provision of medical care as to the choice of the appropriate drugs and their sequential application over the course of the disease. This personalized provision takes patient preferences as well as disease-related factors into consideration such as objective clinical and radiographic findings but also very burdensome symptoms such as fatigue, depression, and cognitive impairment. Future trial designs in MS will have to assign higher relevance to these patient-reported outcomes and will also have to implement surrogate measures that can serve as predictive markers for individual treatment response to new and investigational immunotherapies. This is an indispensable prerequisite to maximize the benefit of individual patients when participating in clinical trials. Moreover, such appropriate trial designs and suitable enrolment criteria that correspond to the mode of action of the study drug will facilitate targeted prevention of adverse events, thus mitigating risks for individual study participants.

Patient-Reported Outcomes in Phase II Cancer Clinical Trials: Lessons Learned and Future Directions

2007 ◽  
Vol 25 (32) ◽  
pp. 5058-5062 ◽  
Author(s):  
Lynne I. Wagner ◽  
Lari Wenzel ◽  
Edward Shaw ◽  
David Cella
Keyword(s):  
Clinical Trials ◽  
Phase Ii ◽  
Symptom Management ◽  
Patient Reported Outcomes ◽  
Phase Iii ◽  
Cancer Clinical Trials ◽  
Phase Ii Trials ◽  
Patient Reported ◽  
Phase Iii Trials ◽  
The Impact

With increasing limits on the resources available to conduct cancer clinical trials, the inclusion of patient-reported outcomes (PROs) in treatment and symptom management trials must be prioritized. Although it has been suggested on occasion that phase III trials should take precedence over phase II trials, we argue that there is a clear and important role for PRO assessment in phase II trials going forward. To illustrate the value realized from including PROs in phase II trials, we provide case examples from cancer treatment and supportive care. The benefits of including PROs in symptom management intervention research are exemplified using phase II trials targeting cognitive impairment. The inclusion of PROs in phase II cancer clinical trials adds important information about the impact of treatment in health-related quality of life, and advances the science of PRO measurement. These contributions significantly enhance the design of phase III trials, ultimately leading to the efficient utilization of clinical trial resources.

A comparison of patient-reported outcomes (PROs) in National Cancer Institute-sponsored cancer treatment trials conducted during two time periods: 1999–2003 and 2003–2008

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 6618-6618
Author(s):  
A. M. O'Mara ◽  
A. M. Denicoff ◽  
B. Reeve ◽  
R. Burns ◽  
T. Trimble
Keyword(s):  
Quality Of Life ◽  
Patient Reported Outcomes ◽  
Phase Iii ◽  
Disease Treatment ◽  
Treatment Trials ◽  
Patient Reported ◽  
Phase Iii Trials ◽  
Secondary Endpoints ◽  
Time Periods

6618 Background: Over the past decade, the U.S. National Cancer Institute (NCI) support for incorporating Patient-Reported Outcomes (PROs) into disease treatment clinical trials has grown considerably, both in the number of trials, as well as the types of research questions being addressed and the measures used to answer the questions. This presentation will compare the breadth of NCI supported Phase III treatment trials in breast, colo-rectal, lung, and prostate cancers that include PRO secondary endpoints activated during two time periods: 1999–2003 and 2003–2008. Both time periods will be compared to identify the number and type of PRO measures; in addition the targeted PRO domain will be examined by cancer site. Methods: For this study, PRO was broadly defined to include any self-report questionnaire that gathered data on the potential impact that disease treatment might have on patient functioning, quality of life, or symptoms. Using the terms, 'protocol title, lead disease, phase III, quality of life, and instrument name,’ a search was conducted of the NCI database containing breast, colo-rectal, lung, and prostate Phase III treatment trials activated during the two time periods. If a scale was used more than once or if different versions of the scale were used, i.e., FACT-G and FACT-BR, it was only counted once. Results: Between 1999 and 2003, 42 phase III trials in the four major cancers were activated, with 15 trials having one or more PROs as secondary endpoints. Between 2003 and 2008, 50 phase III trials in the four major cancers were activated, with 28 trials having one or more PROs as secondary endpoints. Although the data reveal a 20% increase in the number of phase III trials in the 4 diseases between the two time periods, the number of trials with PRO endpoints has doubled. Conclusions: This significant increase in the use of PROs in phase III trials gives investigators additional data to fully analyze the impact of new treatments. These PRO data will provide researchers, clinicians, and future patients with a more in-depth understanding of the potential for new cancer therapies and technologies to extend both the quantity and quality of life. No significant financial relationships to disclose.

scholarly journals Ocrelizumab reduces progression of upper extremity impairment in patients with primary progressive multiple sclerosis: Findings from the phase III randomized ORATORIO trial

2018 ◽  
Vol 24 (14) ◽  
pp. 1862-1870 ◽  
Author(s):  
Edward J Fox ◽  
Clyde Markowitz ◽  
Angela Applebee ◽  
Xavier Montalban ◽  
Jerry S Wolinsky ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Upper Extremity ◽  
Progressive Multiple Sclerosis ◽  
Phase Iii ◽  
Primary Progressive Multiple Sclerosis ◽  
Primary Progressive ◽  
Intention To Treat ◽  
Disability Status ◽  
Upper Extremity Impairment ◽  
Post Hoc

Background: Upper extremity (UE) impairment is common with primary progressive multiple sclerosis (PPMS). Objective: This exploratory analysis examined the effects of ocrelizumab on confirmed progression (CP) and confirmed improvement (CI) in UE impairment in patients from ORATORIO. Methods: Patients with PPMS received ocrelizumab 600 mg or placebo every 24 weeks for ⩾120 weeks. The Nine-Hole Peg Test (9HPT) was administered at baseline (BL) and every 12 weeks thereafter. Prespecified exploratory endpoints included change in 9HPT time and proportion of patients with CP of ⩾20% in 9HPT. Analysis populations included intention-to-treat (ITT) patients and subgroups stratified by BL 9HPT time and Expanded Disability Status Scale. Post hoc analyses included the proportion of patients achieving more severe thresholds of CP and the proportion achieving CI in 9HPT. Results: Among ITT patients, ocrelizumab significantly reduced the change in 9HPT time over 120 weeks, the risk of CP of ⩾20% in 9HPT time for both hands and the risk of more severe 9HPT progression versus placebo. Numerical trends also favoured ocrelizumab versus placebo with respect to achieving CI. Consistent directional trends were observed in subgroup analyses. Conclusion: Ocrelizumab reduces the risk of UE disability progression and may increase the possibility of improvement versus placebo in PPMS.

scholarly journals Disease-modifying treatments for progressive multiple sclerosis

2013 ◽  
Vol 19 (11) ◽  
pp. 1428-1436 ◽  
Author(s):  
Giancarlo Comi
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Progressive Disease ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Laboratory Science ◽  
New Concepts ◽  
Relapsing Remitting ◽  
Relapsing Remitting Multiple Sclerosis ◽  
Major Progress

The last 20 years have seen major progress in the treatment of relapsing–remitting multiple sclerosis (RRMS) using a variety of drugs targeting immune dysfunction. In contrast, all clinical trials of such agents in primary progressive multiple sclerosis (PPMS) have failed and there is limited evidence of their efficacy in secondary progressive disease. Evolving concepts of the complex interplay between inflammatory and neurodegenerative processes across the course of multiple sclerosis (MS) may explain this discrepancy. This paper will provide an up-to-date overview of the rationale and results of the published clinical trials that have sought to alter the trajectory of both primary and secondary MS, considering studies involving drugs with a primary immune target and also those aiming for neuroprotection. Future areas of study will be discussed, building on these results combined with the experience of treating RRMS and new concepts emerging from laboratory science and animal models.

Dalfampridine Extended Release Tablets—Clinical Need and Use

US Neurology ◽  
2010 ◽  
Vol 06 (02) ◽  
pp. 76 ◽  
Author(s):  
Aaron Miller ◽  
Amy Perrin Ross ◽  
James Gilbart ◽  
◽  
◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Potassium Channel ◽  
Drug Administration ◽  
Extended Release ◽  
Channel Blocker ◽  
Phase Iii ◽  
Walking Ability ◽  
Phase Iii Trials ◽  
Walking Speeds

Walking impairment is one of the most serious and frequent problems reported by multiple sclerosis (MS) patients. Treatments to restore walking ability are an unmet clinical need. Dalfampridine, a potassium channel blocker, is the first US Food and Drug Administration (FDA)-approved drug to be indicated specifically to improve walking in patients with MS. In clinical trials the drug showed improved walking speeds, demonstrating efficacy in all four types of MS. In phase III trials, dalfampridine provided significant benefits to 35–43% of treated patients. Therefore, it will be critical to manage patient expectations appropriately.

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