Comparative Effectiveness of 4 Exercise Interventions Followed by 2 Years of Exercise Maintenance in Multiple Sclerosis: A Randomized Controlled Trial

ObjectiveTo determine the effects of exergaming (EXE) on quality of life (QOL), motor, and clinical symptoms in multiple sclerosis (MS). We compared the effects of EXE, balance (BAL), cycling (CYC), proprioceptive neuromuscular facilitation (PNF), and a standard care wait-listed control group on clinical and motor symptoms and quality of life (QOL) in people with MS (PwMS) and determined the effects of subsequent maintenance programs for 2 years in a hospital setting.DesignA randomized controlled trial, using before-after test design.SettingUniversity hospital setting.ParticipantsOf 82 outpatients with MS, 70 were randomized (N=70), and 68 completed the study.InterventionsThe initial high-intensity and high-frequency interventions consisted of 25 one-hour sessions over 5 weeks. After the 5-week-long initial intervention, the 2-year-long maintenance programs followed, consisting of 3 sessions per week, each for 1 hour.Main Outcome MeasuresThe primary outcome: Multiple Sclerosis Impact Scale (MSIS-29). Secondary outcomes: Measures 5 aspects of health-related QOL (EuroQol 5-Dimension questionnaire), Beck Depression Inventory, 6-minute walk test (6MWT), Berg Balance Scale (BBS), Tinetti Assessment Tool (TAT), and static BAL (center of pressure).ResultsMSIS-29 improved most in EXE (11 points), BAL (6), and CYC (6) (all P<.05). QOL improved most in EXE (3 points), CYC, and BAL (2) (all P<.05). TAT and BBS improved significantly (P<.05) but similarly (P>.05) in EXE, BAL, and CYC. 6MWT improved most in EXE (57m), BAL (32m), and CYC (19m) (all P<.001). Standing sway did not change. Maintenance programs further increased the initial exercise-induced gains, robustly in EXE.ConclusionsA total of 25 sessions of EXE, BAL, CYC, and PNF, in this order, improved clinical and motor symptoms and QOL, and subsequent 2-year-long thrice weekly maintenance programs further slowed symptom worsening and improved QOL. EXE was the most and PNF was the least effective to improve clinical symptoms, motor function, and QOL in PwMS.     

Feasibility study design and methods for Project GEMS: Guidelines for Exercise in Multiple Sclerosis

The Guidelines for Exercise in Multiple Sclerosis (GEMS) program is a randomized controlled trial (RCT) examining the feasibility and efficacy of a home-based exercise training program based on recent physical activity guidelines and principles of behavior change for improving symptoms and health-related quality of life (HRQOL) in adults with multiple sclerosis (MS). The primary aim is to assess program feasibility in the four domains of process (e.g., recruitment, retention, and adherence), resources (e.g., communication, staff requirements, and monetary costs), management (e.g., time and accuracy in data collection/entry, and reporting of adverse events) and scientific outcomes (e.g., safety, burden, participant feedback and efficacy/outcomes). The trial will recruit individuals with mild-to-moderate MS-related disability across the United States who will be randomized into intervention or waitlist control conditions. All participants will complete home-based assessments (including wearing an accelerometer for 7 days and completion of a questionnaire booklet) prior to and upon completion of the 4-month program. Participants in the intervention will receive a 4-month home-based exercise program emphasizing aerobic and resistance training. Participants will be provided with exercise equipment, a DVD, a manual and a log-book. The exercise program will be supplemented with periodic newsletters in the mail highlighting principles of behavior change, and video-chats with an exercise specialist to provide motivation and social accountability. This trial serves to inform development of Phase II and III RCTs which can determine the actual efficacy and effectiveness of home-based exercise based on the MS-specific physical activity guidelines for improving symptoms and HRQOL.     

Exercise for methamphetamine dependence: Rationale,design, and methodology

BackgroundEffective pharmacotherapies to treat methamphetamine (MA) dependence have not been identified, and behavioral therapies are marginally effective. Based on behavioral studies demonstrating the potential efficacy of aerobic exercise for improving depressive symptoms, anxiety, cognitive deficits, and substance use outcomes, the study described here is examining exercise as a potential treatment for MA-dependent individuals.MethodsThis study is randomizing 150 participants with MA dependence at a residential treatment facility for addictive disorders to receive either a thrice-weekly structured aerobic and resistance exercise intervention or a health education condition. Recruitment commenced in March, 2010. Enrollment and follow-up phases are ongoing, and recruitment is exceeding targeted enrollment rates.ConclusionsSeeking evidence for a possibly effective adjunct to traditional behavioral approaches for treatment of MA dependence, this study is assessing the ability of an 8-week aerobic and resistance exercise protocol to reduce relapse to MA use during a 12-week follow-up period after discharge from residential-based treatment. The study also is evaluating improvements in health and functional outcomes during and after the protocol. This paper describes the design and methods of the study.     

Balance Exercise Program Reduced Falls in People With Multiple Sclerosis: A Single-Group,Pretest-Posttest Trial

ObjectiveTo evaluate the effects of a balance exercise program on falls in people with mild to moderate multiple sclerosis (MS).DesignMulticenter, single-blinded, single-group, pretest-posttest trial.SettingSeven rehabilitation units within 5 county councils.ParticipantsCommunity-dwelling adults with MS (N=32) able to walk 100m but unable to maintain 30-second tandem stance with arms alongside the body.InterventionSeven weeks of twice-weekly, physiotherapist-led 60-minute sessions of group-based balance exercise targeting core stability, dual tasking, and sensory strategies (CoDuSe).Main Outcome MeasuresPrimary outcomes: number of prospectively reported falls and proportion of participants classified as fallers during 7 preintervention weeks, intervention period, and 7 postintervention weeks. Secondary outcomes: balance performance on the Berg Balance Scale, Four Square Step Test, sit-to-stand test, timed Up and Go test (alone and with cognitive component), and Functional Gait Assessment Scale; perceived limitations in walking on the 12-item MS Walking Scale; and balance confidence on the Activities-specific Balance Confidence Scale rated 7 weeks before intervention, directly after intervention, and 7 weeks later.ResultsNumber of falls (166 to 43; P≤.001) and proportion of fallers (17/32 to 10/32; P≤.039) decreased significantly between the preintervention and postintervention periods. Balance performance improved significantly. No significant differences were detected for perceived limitations in walking, balance confidence, the timed Up and Go test, or sit-to-stand test.ConclusionsThe CoDuSe program reduced falls and proportion of fallers and improved balance performance in people with mild to moderate MS but did not significantly alter perceived limitations in walking and balance confidence.     

Intervention Comparative Effectiveness for Adult Cognitive Training (ICE-ACT) Trial: Rationale,design, and baseline characteristics

Age-related perceptual and cognitive declines are associated with difficulties performing everyday tasks required to remain independent. Encouraging improvements in cognitive abilities have been shown for various short-term interventions but there is little evidence for direct impact on independence. This project compares the effect of broad and directed (narrow) technology-based training on basic perceptual and cognitive abilities in older adults and on the performance of simulated tasks of daily living including driving and fraud avoidance. Participants (N = 230, Mean age = 72) were randomly assigned to one of four training conditions: broad training using either (1) a web-based brain game suite, Brain HQ, or (2) a strategy video game, Rise of Nations, or to directed training for (3) Instrumental Activities of Daily Living (IADL) training using web-based programs for both driving and fraud avoidance training, or (4) to an active control condition of puzzle solving. Training took approximately 15–20 h for each intervention condition across four weeks. Before training began, participants received baseline ability tests of perception, attention, memory, cognition, and IADL, including a driving simulator test for hazard perception, and a financial fraud recognition test. They were tested again on these measures following training completion (post-test). A one-year follow-up from training completion is also scheduled. The baseline results support that randomization was successful across the intervention conditions. We discuss challenges and potential solutions for using technology-based interventions with older adults. We also discuss how the current trial addressed methodological limitations of previous intervention studies.Trial registration numberNCT03141281     

Rationale and design of the Tanzania Vitamin and HIV Infection Trial

We present the rationale and design of a randomized, double-blind, placebo-controlled trial of vitamin supplements among HIV-positive pregnant women in Dar es Salaam, Tanzania. Higher levels of intake of vitamins A, B, C, and E may decrease the risk of vertical transmission and progression of HIV infection by enhancing maternal and infant immune function; by reducing viral load in the blood, breast milk, or lower genital tract secretions; and/or by strengthening the placental barrier to infection. Eligible pregnant women were randomized to receive vitamin A, multivitamins excluding A, vitamin A and multivitamins, or placebo. The main endpoints include vertical transmission of HIV infection, as assessed by examination of infection in infants using polymerase chain reaction (PCR), and progression of HIV disease as measured by the WHO clinical staging system. Over a period of 2 years, 13,876 women were tested for HIV infection, with appropriate pre- and posttest counseling, to enroll 1085 consenting HIV-positive women. The trial assesses women and their children once a month for a minimum of 18 months after delivery or up to the end of this 5-year study. We examine recruitment strategies and means of enhancing cohort retention in long-term follow-up. We assess compliance with the use of supplements by direct questioning, by counting pills, and biochemically by using serum beta-carotene and urine riboflavin levels. Briefly, we discuss ethical issues related to the conduct of AIDS prevention trials in this setting. In sub-Saharan Africa, most HIV-infected persons lack access to the relevant antiretroviral and prophylactic drugs, and the region urgently needs low-cost treatments and preventive strategies. The Tanzania trial should provide valuable data to address the effect of vitamin supplements in the transmission and progression of HIV infection.     

Effect of Exercise on Fatigue in Multiple Sclerosis: A Network Meta-analysis Comparing Different Types of Exercise

ObjectiveA network meta-analysis (NMA) of current evidence was conducted to determine if physical exercise has a positive influence on multiple sclerosis (MS) fatigue and type of exercise with the largest effect on fatigue also according to disease severity.Data SourcesMEDLINE, Embase, SPORTDiscus, Physiotherapy Evidence Database, Cochrane Library, and Web of Science. The search strategy combined relevant terms related to (1) MS; (2) clinical trials; (3) exercise; and (4) fatigue from inception to February 2021.Study SelectionRandomized controlled trials concerning the effectiveness of different types of exercise on total and physical fatigue in people with MS were included.Data ExtractionThe data were extracted into predesigned data extraction tables. Risk of bias was evaluated with the Cochrane Risk of Bias tool (RoB 2.0), and the Grading of Recommendations, Assessment, Development, and Evaluation tool was used to evaluate the quality of the evidence.Data SynthesisA total of 58 studies were examined. Data were pooled using a random-effects model. A ranking of 7 and 8 different exercise interventions for physical and total fatigue scores, respectively, was achieved. The highest effects for pairwise comparisons were for combined exercise and resistance training vs control (ranging between ?0.74 and ?1.24). In the NMA, combined exercise (?1.51; 95% confidence interval [CI], ?2.01 to ?1.01) and resistance training (?1.15; 95% CI, ?1.81 to ?0.49) compared with the control group achieved the highest effects for physical and total fatigue, respectively.ConclusionsExercise should be considered an effective fatigue management strategy. Among the different exercise modalities, combined exercise is the most effective exercise modality for improving both physical and total fatigue. Resistance training is also an effective exercise for total fatigue among people diagnosed with MS.     

PCI Alternative Using Sustained Exercise (PAUSE): Rationale and trial design

Cardiovascular disease (CVD) currently claims nearly one million lives yearly in the US, accounting for nearly 40% of all deaths. Coronary artery disease (CAD) accounts for the largest number of these deaths. While efforts aimed at treating CAD in recent decades have concentrated on surgical and catheter-based interventions, limited resources have been directed toward prevention and rehabilitation. CAD is commonly treated using percutaneous coronary intervention (PCI), and this treatment has increased exponentially since its adoption over three decades ago. Recent questions have been raised regarding the cost-effectiveness of PCI, the extent to which PCI is overused, and whether selected patients may benefit from optimal medical therapy in lieu of PCI. One alternative therapy that has been shown to improve outcomes in CAD is exercise therapy; exercise programs have been shown to have numerous physiological benefits, and a growing number of studies have demonstrated reductions in mortality. Given the high volume of PCI, its high cost, its lack of effect on survival and the potential for alternative treatments including exercise, the current study is termed “PCI Alternative Using Sustained Exercise” (PAUSE). The primary aim of PAUSE is to determine whether patients randomized to exercise and lifestyle intervention have greater improvement in coronary function and anatomy compared to those randomized to PCI. Coronary function and anatomy is determined using positron emission tomography combined with computed tomographic angiography (PET/CTA). Our objective is to demonstrate the utility of a non-invasive technology to document the efficacy of exercise as an alternative treatment strategy to PCI.     

Trial of calcium for preeclampsia prevention (CPEP): Rationale,design, and methods

The results of ten clinical trials suggest that supplemental calcium may prevent preeclampsia. However, methodologic problems and differences in study design limit the acceptance of the results and their relevance to other patient populations. Many of the trials were conducted in countries where, unlike the United States, the usual daily diet contained little calcium. Moreover, none of the trials has reported the outcome of systematic surveillance for urolithiasis, a potential complication of calcium supplementation. In response to the need for a thorough evaluation of the effects of calcium supplementation for the prevention of preeclampsia in the United States, the trial of Calcium for Preeclampsia Prevention (CPEP) was undertaken at five university medical centers. Healthy nulliparous patients were randomly assigned to receive either 2 g supplemental calcium daily (n = 2295) or placebo (n = 2294) in a double-blind study. Study tablets were administered beginning from 13 to 21 completed weeks of gestation and continued until the termination of pregnancy. CPEP employed detailed diagnostic criteria, standardized techniques of measurement, and systematic surveillance for the major study endpoints and for urolithiasis. The nutrient intake of each patient was assessed at randomization and at 32–33 weeks gestation. This report describes the study rationale, design, and methods.     

Rationale and design of the Atrial Fibrillation health Literacy Information Technology Trial: (AF-LITT)

BackgroundAtrial Fibrillation (AF) is a common cardiac arrhythmia that is challenging for patients and adversely impacts health-related quality of life (HRQoL). Long-term management of AF requires that patients adhere to complex therapies, understand difficult terminology, navigate subspecialty care, and have continued symptom monitoring with the goal of preventing adverse outcomes. Continued interventions to ameliorate the patient experience of AF are essential.DesignThe Atrial Fibrillation health Literacy Information Technology Trial (AF-LITT; NCT03093558) is an investigator-initiated, 2-arm randomized clinical trial (RCT). This RCT is a pilot in order to implement a novel, smartphone-based intervention to address the patient experience of AF. This pilot RCT will compare a combination of the Embodied Conversational Agent (ECA) and the Alive Cor Kardia Mobile heart rhythm monitor to the current standard of care. The study will enroll 180 adults with non-valvular AF who are receiving anticoagulation for stroke prevention and randomize them to receive a 30-day intervention (smartphone-based ECA/Kardia) or standard of care, which will include a symptom and adherence journal. The primary end-points are improvement in HRQoL and self-reported adherence to anticoagulation. The secondary end-points are the acceptability of the intervention to participants, its use by participants, and acceptability to referring physicians.ConclusionsThe AF-LITT pilot aims to evaluate the efficacy of the ECA/Kardia to improve HRQoL and anticoagulant adherence, and to guide its implementation in a larger, multicenter clinical trial. The intervention has potential to improve HRQoL, adherence, and health care utilization in individuals with chronic AF.     

Rationale and Design of the Informing Fresh versus Old Red Cell Management (INFORM) Trial: An International Pragmatic Randomized Trial

Although red blood cell transfusion is a potentially lifesaving intervention in severely anemic and acutely bleeding patients, some observational studies have suggested that prolonged red cell storage before transfusion is associated with harm. INFORM is a large, pragmatic, randomized controlled trial comparing the effect of the shorter storage with longer storage red blood cell transfusions on inhospital mortality in hospitalized patients who require a blood transfusion. The trial is being conducted in centers in Australia, Canada, Israel, and the United States and is expected to enroll 31 497 patients. If the results of INFORM indicate that shorter storage red blood cell transfusion is associated with superior outcomes compared with standard issue red blood cell transfusion, consideration may be given to shortening blood storage times. If, in contrast, the INFORM trial provides no evidence of harm from longer storage red blood cells, clinicians and patients may be reassured that current blood inventory management strategies are appropriate.     

Rationale and design of the Chronic Kidney Disease Antidepressant Sertraline Trial (CAST)

Major Depressive Disorder (MDD) affects one in five patients with Chronic Kidney Disease (CKD) and is an independent risk factor for hospitalization and death before and after dialysis initiation. However, it remains an under-recognized and under-treated problem, in part due to the lack of well-controlled studies that support or refute the efficacy and safety of antidepressant medications in CKD patients. Major trials of antidepressant treatment excluded patients with stages 3–5 CKD, precisely those at higher risk for both depression and increased mortality. The Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) is a randomized, double-blinded, placebo-controlled trial of sertraline, a selective serotonin reuptake inhibitor (SSRI). It will enroll 200 adults with stages 3–5 CKD and MDD excluding kidney transplant and chronic dialysis patients. Sertraline will be administered at an initial dose of 50 mg once daily or matching placebo followed by a dose escalation strategy consisting of 50 mg increments at 2 week intervals (as tolerated) to a maximum dose of 200 mg. The primary outcome is improvement in depression symptom severity measured by the Quick Inventory of Depressive Symptomatology scale. Secondary outcomes include safety endpoints and improvement in quality of life. Changes in cognitive function, adherence to medications, nutritional status, inflammation, and platelet function will be explored as potential mechanisms by which depression may mediate poor outcomes. We discuss the rationale and design of the CAST study, the largest placebo-controlled trial aimed to establish safety and efficacy of a SSRI in the acute phase treatment of CKD patients with MDD.     

Efficacy and Safety of Fingolimod in Hispanic Patients with Multiple Sclerosis: Pooled Clinical Trial Analyses

Introduction

The disease characteristics of multiple sclerosis (MS) appear to differ between Hispanic and Caucasian patients, with Hispanic patients having a younger age at onset, and a higher prevalence of optic nerve and spinal cord involvement. Fingolimod, the first-in-class oral sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing MS, has been shown to significantly reduce annualized relapse rates (ARRs), lesion-based magnetic resonance imaging (MRI) activity, confirmed disability, and brain volume loss, compared with placebo or intramuscular interferon beta-1a (IFNβ-1a IM) in randomized, double-blind, controlled clinical studies. Here, the efficacy and safety profile of fingolimod in Hispanic patients was compared to that observed in the overall study populations.

Methods

This was a post hoc analysis of relapses and safety data for Hispanic patients with relapsing–remitting MS (RRMS) randomized to receive daily fingolimod 0.5 mg, weekly IFNβ-1a IM (30 mg) or placebo, in the phase 3, controlled FREEDOMS, FREEDOMS II, and TRANSFORMS fingolimod studies. The ARR was estimated for each treatment group; only relapses that were confirmed by an independent examining neurologist were included in these analyses. Safety assessments included the incidence of adverse events and serious adverse events.

Results

Eligible Hispanic patients aged 18–55 years (n = 181) had been treated as follows: fingolimod 0.5 mg (n = 89), IFNβ-1a IM (n = 65), and placebo (n = 27). Hispanic patients treated with fingolimod for up to 2 years had lower ARRs (ARR: 0.22, 95% confidence interval [CI]: 0.14–0.35) than those receiving placebo (ARR: 0.46, 95% CI: 0.24–0.88) or IFNβ-1a IM (ARR: 0.34, 95% CI: 0.18–0.63), with relative reductions of 52% and 35%, respectively. A transient decrease in heart rate that started to attenuate 6 h after fingolimod administration was observed, consistent with the well-characterized pharmacologic effect following fingolimod treatment initiation. No cases of symptomatic bradycardia were reported in Hispanic patients. The incidence of first-degree atrioventricular block was low and similar across all treatment groups (3.1–4.5%). The safety profile of fingolimod in Hispanic patients was consistent with that reported in the overall population of each study.

Conclusion

Overall, this study demonstrates that fingolimod is efficacious and well tolerated in Hispanic patients with RRMS.     

Validation of the Multidimensional Outcome Expectations for Exercise Scale in Ambulatory, Symptom-Free Persons With Multiple Sclerosis

McAuley E, Motl RW, White SM, Wójcicki TR. Validation of the Multidimensional Outcome Expectations for Exercise Scale in ambulatory, symptom-free persons with multiple sclerosis.

Objective

To determine the psychometric properties of the 3-factor Multidimensional Outcome Expectations for Exercise Scale in a sample of ambulatory, symptom-free persons with multiple sclerosis (MS).

Design

Cross-sectional validation study.

Setting

Midwestern university.

Participants

Community-dwelling adults (N=242) with an established definite diagnosis of MS, as corroborated by the participant's neurologist, who were relapse free for the last 30 days and ambulatory with minimal assistance.

Interventions

Not applicable.

Main Outcome Measures

Multidimensional Outcome Expectations for Exercise Scale, physical activity, self-efficacy, and physical health status. Confirmatory factor analyses using covariance modeling and correlational analyses were used to establish factorial and construct validity.

Results

Analyses showed excellent factorial validity for the hypothesized factor structure reflecting physical, social, and self-evaluative outcome expectations. All 3 subscales were internally consistent. Theoretically, relevant correlations between outcome expectations and self-efficacy, physical activity, and physical health status were all supported.

Conclusions

The Multidimensional Outcome Expectations for Exercise Scale appears to be a reliable and valid measure of outcome expectations for exercise in this limited sample of community-dwelling adults with MS. Further validation in clinical samples is warranted.     

2nd International Symposium on Gait and Balance in Multiple Sclerosis: interventions for gait and balance in MS

Abstract

Purpose: To provide a review of the 2nd International Symposium on Gait and Balance in Multiple Sclerosis (MS), emphasizing interventions in gait and balance for people with MS. Method: Review of current research on interventions used with people having MS and with people having other disorders that may provide novel insights into improving gait and balance and preventing falls in people with MS (pwMS). Results: Nine speakers provided evidence-based recommendations for interventions aimed at improving gait and balance dysfunction. Speaker recommendations covered the following areas: balance rehabilitation, self-management, medications, functional electrical stimulation, robotics, sensory augmentation, gait training with error feedback and fall prevention. Conclusions: The causes of gait and balance dysfunction in pwMS are multifactorial and therefore may benefit from a wide range of interventions. The symposium provides avenues for exchange of evidence and clinical experience that is critical in furthering physical rehabilitation including gait and balance dysfunction in MS.

• Implications for Rehabilitation

• Approaches to improve Gait and Balance dysfunction in Multiple Sclerosis.

• Balance exercises that include training of sensory strategies.

• Self-management and self-management support.

• Pharmacologic intervention, such as Dalfampradine.

• Functional electrical stimulation that may provide the extra stimulation to influence coordinated leg movements needed for walking.

     

The MeTeOR Trial (Meniscal Tear in Osteoarthritis Research): Rationale and design features

This paper presents the rationale and design features of the MeTeOR Trial (Meniscal Tear in Osteoarthritis Research; Clinical Trials.gov NCT00597012). MeTeOR is an NIH-funded seven-center prospective randomized controlled trial (RCT) designed to establish the efficacy of arthroscopic partial meniscectomy combined with a standardized physical therapy program as compared with a standardized physical therapy program alone in patients with a symptomatic meniscal tear in the setting of mild to moderate knee osteoarthritic change (OA). The design and execution of a trial that compares surgery with a nonoperative treatment strategy presents distinctive challenges. The goal of this paper is to provide the clinical rationale for MeTeOR and to highlight salient design features, with particular attention to those that present clinical and methodologic challenges.     

The MeTeOR Trial (Meniscal Tear in Osteoarthritis Research): Rationale and design features

This paper presents the rationale and design features of the MeTeOR Trial (Meniscal Tear in Osteoarthritis Research; Clinical Trials.gov NCT00597012). MeTeOR is an NIH-funded seven-center prospective randomized controlled trial (RCT) designed to establish the efficacy of arthroscopic partial meniscectomy combined with a standardized physical therapy program as compared with a standardized physical therapy program alone in patients with a symptomatic meniscal tear in the setting of mild to moderate knee osteoarthritic change (OA). The design and execution of a trial that compares surgery with a nonoperative treatment strategy presents distinctive challenges. The goal of this paper is to provide the clinical rationale for MeTeOR and to highlight salient design features, with particular attention to those that present clinical and methodologic challenges.