Time to first relapse as an endpoint in multiple sclerosis clinical trials

Background: The increasing number of effective therapies to treat multiple sclerosis (MS) raises ethical concerns for the use of placebo in clinical trials, suggesting that new clinical trial design strategies are needed. Objectives: To evaluate time to first relapse as an endpoint for MS clinical trials. Methods: A recently-developed model fitting the distribution of time to first relapse in MS was used for simulations estimating the sample sizes of trials using this as an outcome, and for comparison with the size of trials using the annualized relapse rate (ARR) as the primary outcome. Results: Trials based on time to first relapse were feasible, requiring sample sizes that were similar or even smaller than if the study was based on ARR instead. In the case of low ARR (0.4 relapses/year), as is expected in future trials, the 1-year trials designed to detect a treatment effect of 30%, with 90% power, require fewer patients when based on time to first relapse (470 patients/arm) than if based on ARR (540 patients/arm). Conclusions: Our simulations show that time to first relapse is not less powerful than ARR in MS trials; thus, this measure would be a potentially useful primary outcome offering the advantage of an ethically sound design, as the patients randomized to placebo can then switch to the active drug, once they relapse. A potential drawback is the loss of information for other endpoints collected at fixed time points.

Download Full-text

Digital Technology in Clinical Trials for Multiple Sclerosis: a systematic review. (Preprint)

10.2196/preprints.20670 ◽

2020 ◽

Author(s):

Marcello De Angelis ◽

Luigi Lavorgna ◽

Antonio Carotenuto ◽

Martina Petruzzo ◽

Roberta Lanzillo ◽

...

Keyword(s):

Multiple Sclerosis ◽

Clinical Trial ◽

Clinical Trials ◽

Outcome Measures ◽

Digital Technology ◽

Clinical Trial Design ◽

Motor Rehabilitation ◽

Robot Assisted ◽

Future Directions ◽

Treatment Side Effects

BACKGROUND Clinical trials in multiple sclerosis (MS) have leveraged the use of digital technology to overcome limitations in treatment and disease monitoring. OBJECTIVE To review the use of digital technology in concluded and ongoing MS clinical trials. METHODS In March 2020, we searched for “multiple sclerosis” and “trial” on pubmed.gov and clinicaltrials.gov using “app”, “digital”, “electronic”, “internet” and “mobile” as additional search words, separately. Overall, we included thirty-five studies. RESULTS Digital technology is part of clinical trial interventions to deliver psychotherapy and motor rehabilitation, with exergames, e-training, and robot-assisted exercises. Also, digital technology has become increasingly used to standardise previously existing outcome measures, with automatic acquisitions, reduced inconsistencies, and improved detection of symptoms. Some trials have been developing new patient-centred outcome measures for the detection of symptoms and of treatment side effects and adherence. CONCLUSIONS We will discuss how digital technology has been changing MS clinical trial design, and possible future directions for MS and neurology research.

Download Full-text

Problems in Clinical Trial Design in Multiple Sclerosis

International Journal of MS Care ◽

10.7224/1537-2073-4.3.125 ◽

2002 ◽

Vol 4 (3) ◽

pp. 125-138 ◽

Cited By ~ 1

Author(s):

Jeffrey I. Greenstein

Keyword(s):

Multiple Sclerosis ◽

Clinical Trials ◽

Outcome Measures ◽

Trial Design ◽

Clinical Trial Design ◽

Evidence Based ◽

Controlled Clinical Trials ◽

Cognitive Components ◽

Basic Understanding ◽

Clinical Measures

Historically, it has been difficult to demonstrate the effectiveness of treatments for multiple sclerosis (MS) because of the variability in the course of the disease, the lack of well-defined, reliable clinical measures, and the pervasiveness of poorly controlled clinical trials. Hence, to interpret the results of clinical trials in MS and make evidence-based decisions regarding treatment for their patients, neurologists should have a basic understanding of appropriate outcome measures and the necessary controls of a well-designed study. This paper reviews the controls required to test the efficacy of agents for the treatment of MS and offers examples of poorly controlled clinical trials to illustrate the problems in interpreting data without such controls. In addition, the outcome measures that should be used to assess the efficacy of treatments on the physical, inflammatory, and cognitive components of the disease are discussed. (Int J MS Care. 2002; 4: 125–131, 136–137)

Download Full-text

Cancer

Handbook of Research on Advancements in Cancer Therapeutics - Advances in Medical Diagnosis, Treatment, and Care ◽

10.4018/978-1-7998-6530-8.ch024 ◽

2021 ◽

pp. 627-638

Author(s):

Rashi Rai ◽

Prudhvilal Bhukya ◽

Muneesh Kumar Barman ◽

Meenakshi Singh ◽

Kailash Chand ◽

...

Keyword(s):

Artificial Intelligence ◽

Clinical Trial ◽

Clinical Trials ◽

Trial Design ◽

Clinical Trial Design ◽

Success Rates ◽

Design Strategies ◽

Safety Level ◽

Key Steps ◽

The Impact

Clinical trials are essential to govern the impact of a new possible treatment. It is utilized to determine the safety level and efficacy of a certain treatment. Clinical trial studies in cancer have provided successful treatment leading to longer survival span in the patients. The design of clinical trials for cancer has been done to find new ways to prevent, diagnose, treat, and manage symptoms of the disease. This chapter will provide detailed information on different aspects of clinical trials in cancer research. Protocols outlining the design and method to conduct a clinical trial in each phase will be discussed. The process and the conditions applied in each phase (I, II, and III) will be described precisely. The design of trials done in every aspect such as prevention, immunochemotherapy, diagnosis, and treatment to combat cancer will be illustrated. Also, recent innovations in clinical design strategies and principles behind it as well as the use of recent advances in artificial intelligence in reshaping key steps of clinical trial design to increase trial success rates.

Download Full-text

Why non-inferiority is more challenging than superiority?

Multiple Sclerosis Journal ◽

10.1177/1352458517703805 ◽

2017 ◽

Vol 23 (6) ◽

pp. 790-791 ◽

Cited By ~ 1

Author(s):

Maria Pia Sormani

Keyword(s):

Multiple Sclerosis ◽

Clinical Trials ◽

Sample Sizes ◽

Superiority Trials

Demonstrating non-inferiority in clinical trials is usually more challenging than showing superiority. In multiple sclerosis (MS), non-inferiority trials are rarely designed since they would require prohibitive sample sizes. In this brief report, the reasons why non-inferiority trials are usually larger than superiority trials is explored.

Download Full-text

Persistent T1 hypointensity as an MRI marker for treatment efficacy in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458507087842 ◽

2008 ◽

Vol 14 (6) ◽

pp. 764-769 ◽

Cited By ~ 23

Author(s):

IJ van den Elskamp ◽

J Lembcke ◽

V Dattola ◽

K Beckmann ◽

C Pohl ◽

...

Keyword(s):

Multiple Sclerosis ◽

Black Hole ◽

Phase Ii ◽

Primary Outcome ◽

Negative Binomial ◽

Outcome Measure ◽

Primary Outcome Measure ◽

Cumulative Number ◽

Sample Sizes ◽

Simulation Procedure

Background MRI is often used as primary outcome measure in phase II clinical trials in multiple sclerosis (MS). Since persistent T1 hypointense lesions are a surrogate parameter for axonal damage and demyelination, they may serve as a marker for monitoring the efficacy of neuroprotective drugs. At present, a power analysis using black hole (BH) evolution as primary outcome measure has not been performed. Objective To assess the feasibility of using BH evolution on serial brain MR images as primary outcome measure in proof of concept studies in MS. Methods MRI-data obtained from 169 active RRMS patients were analysed for BH evolution by determining the cumulative number of contrast enhancing lesions (CEL) evolving into a persistent black hole (PBH) after 3 months. With a parametric simulation procedure, based on a statistical distribution fitting the data, sample sizes were calculated. Results 21.2% of the total number of CELs observed during the study period evolved into a PBH. Ring enhancing lesions evolved most frequently into a PBH (59.4%), followed by lesions larger than 10 mm (57.4%) and periventricular CELs (30.6%). The simulation procedure, based on the statistical negative binomial (NB) model resulted in a sample sizes between 200 subjects and 30 subjects per arm, for treatment effects ranging from 50% to 90% reduction of the number of CELs evolving into a PBH, respectively. Conclusion To perform a MRI monitored phase II clinical trial with a feasible sample size, using the evolution of CELs into PBHs as primary outcome parameter, a potent drug is required to obtain sufficient power.

Download Full-text

Clinical trial design for progressive MS trials

Multiple Sclerosis Journal ◽

10.1177/1352458517729461 ◽

2017 ◽

Vol 23 (12) ◽

pp. 1642-1648 ◽

Cited By ~ 7

Author(s):

Matteo Pardini ◽

Gary Cutter ◽

Maria Pia Sormani

Keyword(s):

Multiple Sclerosis ◽

Clinical Trial ◽

Clinical Trials ◽

Trial Design ◽

Clinical Trial Design ◽

Progressive Multiple Sclerosis ◽

Phase 2 ◽

The Right ◽

Selection Of Patients ◽

Selection Of

The design of clinical trials is a key aspect to maximizing the possibility to detect a treatment effect. This fact is particularly challenging in progressive multiple sclerosis (PMS) studies due to the uncertainty about the right target and/or outcome in phase-2 studies. The aim of this review is to evaluate the current challenges facing the design of clinical trials for PMS. The selection of patients, the instrumental and clinical outcomes that can be used in PMS trials, and issues in their design will be covered in this report.

Download Full-text