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Gastrointestinal Tolerability of Delayed-Release Dimethyl Fumarate in a Multicenter, Open-Label Study of Patients with Relapsing Forms of Multiple Sclerosis (MANAGE)

From Direccion Nacional de Sanidad Policial, CASMU IAMPP, Hospital Británico, Montevideo, Uruguay (VR) and Clinica Colombia, Hospital San Jose, Bogotá, Colombia. 

Valeria Rocha, MD, Morales 2560, 2nd floor. Neurology. Montevideo, Uruguay 11600; 

Latin America (LATAM) is a diverse region with more than 30 countries, each varying in cultural, economic, and social aspects. While multiple sclerosis (MS) care in LATAM has improved, there are still challenges to address. Epidemiologic studies have shown varying incidence rates of MS in the region, influenced by factors such as genetics, environmental conditions, and regional diversity. Scientific research on MS in LATAM has increased, with publications and consensus guidelines emerging. However, access to disease-modifying treatments remains a significant challenge in many countries due to affordability issues and limited availability of certain therapies. The region also faces obstacles in providing comprehensive MS care, including rehabilitation programs and diagnosis tools. There are collaborative efforts and initiatives in LATAM that are working toward overcoming these challenges and improving the overall quality of care for people with MS in the region.

The authors have declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Latin America (LATAM) is a large region comprising most of the American continental mass. It is located between the northern borders of Mexico and the archipelago of Tierra del Fuego in Argentina and includes the Caribbean islands. Its more than 30 countries differ widely in cultural, ethnic, economic, political, religious, and social aspects, making LATAM a heterogeneous region.

Multiple sclerosis (MS) care has significantly improved in LATAM in recent years. However, there is still much to be done. In October 2024, we surveyed via email MS neurologists from many LATAM countries to gain better insight into the region's perceived strengths and difficulties. The survey included questions about the availability of disease-modifying treatments (DMTs), neurorehabilitation, MS centers, and MS patient associations, the use of generic drugs, and whether patients participated in clinical trials. Neurologists from 14 countries were invited to collaborate and responses were collected from 8: Argentina, Bolivia, Chile, Colombia, Ecuador, Paraguay, Peru, and Uruguay. Additional information sources, such as the Atlas of MS and published data, were also consulted to broaden knowledge.

Historically, data-based information on the epidemiology of MS in LATAM has been scarce, particularly in Central American and Caribbean countries, resulting in limited data availability for clinicians, researchers, and patients.

 MS in LATAM populations exhibits distinct characteristics when compared with populations in Europe and North America. The prevalence and incidence of MS in LATAM are lower than those in Northern Europe and North America.

 A systematic review of the disease's epidemiology in LATAM found that the reported incidence ranged from 0.15 to 3 cases per 100,000 person-years, and prevalence ranged from 0.75 to 38.2 cases per 100,000 inhabitants in the 13 studies analyzed.

 The prevalence varies, with higher rates in regions with greater European ancestry (eg, Argentina, Chile, Brazil, Uruguay, and Mexico).

 Unlike in northern latitudes, there is less correlation between latitude and MS prevalence in LATAM.

Several factors contribute to incidence rates of MS in LATAM. Epidemiological studies

 show an extremely low prevalence of MS among Amerindians; this has been attributed to protective ancestral Asian genetics and, possibly, environmental factors. Multiracial Latin Americans of indigenous ancestry and biracial Latin Americans of African ancestry have more susceptibility to MS, which some studies say is due to the historical introduction of the European 

 Another significant finding highlighted the prevalence of vitamin D deficiency among populations living in regions with high ultraviolet radiation (UVR), such as Ecuador, where up to 70% of the general population was reported deficient in serum 25-hydroxyvitamin D.

 This deficiency persists despite the tropical climate, which is generally associated with adequate UVR exposure necessary for vitamin D synthesis.

 Other studies suggest that characteristics unique to LATAM, such as geographical diversity and socioeconomic factors, may explain regional differences in MS prevalence and incidence. Continued exploration of local environmental factors is essential to understand their impact on MS and to develop targeted interventions.

 Some data have shown a lower prevalence of progressive forms of MS in LATAM

; however, this is not a consistent observation.

 The age of onset is similar for people from LATAM to that reported for people from northern hemisphere regions.

 Clinical features are comparable across LATAM, European, and African cohorts.

 One difference is that optic neuritis seems to occur less frequently among LATAM patients.

 However, no strong evidence indicates systematic differences in the clinical presentation and severity

 of MS in LATAM compared to high-prevalence regions; further research is necessary in this area.

In the past, clinical research on MS in LATAM did not focus on local needs and priorities

; however, this is changing. According to PubMed, the National Library of Medicine's database, the number of MS papers published by LATAM researchers has risen exponentially since 2010

 and research from LATAM groups is being published in high-profile scientific publications.

The creation of MS consensus guidelines has also increased in the last few years and now exist in LATAM countries like Argentina, Brazil, Mexico, and Peru.

 There are also joint publications on consensus statements with participants from many LATAM countries.

 Despite this, LATAM populations are not usually included in clinical trials: Only respondents from Argentina, Brazil, Chile, Colombia, Peru, and Mexico reported current or past involvement when asked about participation in phase 3 clinical trials. Finally, the Latin American Committee for Treatment and Research in Multiple Sclerosis (LACTRIMS), founded in 1999, has facilitated LATAM meetings and publications from collaborations.

Much of the data provided by adult MS patients for the 2017 McDonald criteria came from people with Western European genetic or ethnic backgrounds who presented with typical symptoms.

 Validation of the 2017 McDonald criteria has not been widely conducted in LATAM, and there is uncertainty regarding their applicability across LATAM countries.

 Therefore, it is strongly recommended that other regional diseases, such as certain infectious and nutritional conditions that could mimic MS, be ruled out.

In LATAM, more than 70% of people with MS reported visiting at least 2 neurologists before being diagnosed, except respondents from Peru (59.9%). A self-reported patient survey conducted by Carnero and colleagues

 reported that 53% (Honduras) to 96% (Argentina and Costa Rica) of people with MS have complete or partial health insurance coverage for brain and/or spinal cord MRI. Similar results were reported for evoked potential tests and lumbar puncture (LP). In all countries, MRI was the most frequently used tool to establish MS diagnosis (nearly 100% of cases), but differences were found in the frequency of MRI use during follow-up. Rates of LP varied significantly, with ranges as low as 38% (Guatemala) to as high as 85.5% (Costa Rica).

Many countries in LATAM have difficulty providing recommended MS health care due to multiple factors, including delays in access, a shortage of neurologists, segmented health care systems, and restricted economic resources.

 MS is a complex disease, not only because of diagnostic difficulties, multiple disease phenotypes, risk of disability accumulation, and multiple symptomatic manifestations, but also because of the availability of many DMTs with different mechanisms of action, adverse events profiles, and follow-up requirements.

 This has led to the growing importance of MS centers, which provide comprehensive care to patients with MS. A panel of MS neurologists has made recommendations for LATAM MS care unit objectives, human and technical resources, and general functioning.

 Of the surveyed countries, respondents from Argentina, Bolivia, Brazil, Chile, Colombia, Mexico, Paraguay, and Ecuador reported the presence of MS care units.

Optimal management of MS requires multidimensional approaches that involve symptomatic treatment of chronic neurological symptoms that arise from disability accumulation.

 Accordingly, access to rehabilitation (eg, physical, cognitive, occupational) is often necessary during the disease course and should be considered as part of the continuum of care for people with MS. However, accessing neurorehabilitation in LATAM is difficult. Although some types of rehabilitation are provided by most of the public and private health systems, the programs are not MS specific. Cognitive rehabilitation is very limited and, when available, is expensive, and these costs are often the patient's responsibility. In a LATAM patient survey, 16.8% to 56% reported their insurance did not cover physical therapy, and, except for Ecuador (48%), less than 30% had access to outpatient rehabilitation at a specialized center.

 These results align with those reported by the neurologists consulted for this paper; only the neurologist from Ecuador reported broad access to both physical and cognitive rehabilitation. Access to rehabilitation is still one of the biggest roadblocks to MS care in LATAM. A regional cohort survey identified disparities in access to health care services, rehabilitation, and prescription of DMTs and much more unemployment, which may affect access to necessary treatments and care.

 Fortunately, almost all LATAM countries have patient and family associations related to the Multiple Sclerosis International Federation.

Access to DMTs in LATAM poses significant challenges

 as availability differs markedly between upper-middle, middle, lower-middle, and low-income countries, mainly due to high cost. In lower-middle and low-income countries, affordability is the most common cause of lack of access to treatment. In a 2020 survey of people with MS from 12 LATAM countries, between 2.8% and 21.9% of respondents reported DMT accessibility problems because of insurance.

 The armamentarium of DMTs has grown exponentially in the last 14 years; however, not all US Food and Drug Administration–approved therapies are widely available in LATAM. According to the MS Atlas, 94% of countries from the Americas report accessibility barriers.

 In most LATAM countries, oral DMTs and most platform injectable DMTs are available, except for pegylated interferons, which are available only in Argentina and Chile. Availability of monoclonal antibodies and immune reconstitution therapies has also increased recently. Treatments for acute relapses, such as intravenous steroids and plasmapheresis, are also widely available.

 Aspects of MS care in LATAM, including the availability of DMTs, are summarized in the 

. It is important to acknowledge the significant variability in DMT availability within a country's health care system, depending on whether it is in the public or private sector. This was particularly evident in some of the surveyed countries, such as Bolivia, Ecuador, and Peru.

Use of generic and biosimilar drugs has become widespread in LATAM. In Argentina, Chile, Colombia, Honduras, Mexico, and Uruguay, DMTs are frequently switched during treatment for different compounds with the same active ingredient but with a different trademark. This drug's price may be up to 40% less than the original compound,

 improving affordability and patient access. Regulations that guarantee the safety, efficacy, and quality of these drugs are scarce due to the prioritization of economic factors and, therefore, these treatments may be risky for patients with MS.

 Many countries of the region have already included biosimilar and generic formulations of interferons, fingolimod, dimethyl fumarate, teriflunomide, and rituximab in their portfolio of MS therapies. Argentina, Chile, Colombia, Ecuador, Paraguay, Peru, Uruguay, and Venezuela have several of these formulations listed as DMTs, which regulatory agencies usually prefer. When asked, our colleagues have reported both positive and negative aspects of generic use. The greater access patients have to treatment is the most marked positive aspect. However, negative aspects, such as more frequent adverse events, lack of bioequivalence studies, unknown efficacy, and lack of pharmacovigilance, make generic use less attractive. The existence of generics and biosimilars in institutional formularies has not led to substantial cost savings, however, and local licensing agencies need to improve their evaluations of these medicines for the crucial purpose of improving patient outcomes.

 Autologous hematopoietic stem cell transplantation (AHSCT) is a novel MS treatment that is supported by growing but still inconclusive evidence.

 Experience with AHSCT in LATAM is limited but starting to emerge. Some centers in Mexico

 have reported using it and are conducting research.

Despite the evidence showing that high-efficacy treatments (HETs) are more effective in suppressing or delaying relapse when initiated early after disease onset,

 few data exist regarding people with MS who are treated with HETs in LATAM. One notable exception, Alonso et al reported a rapid increase in the use of HETs in clinical practice in the treatment of patients with RRMS in Argentina.

Even though the landscape of MS care in LATAM is evolving, and patients are getting more access to comprehensive MS care and treatment now than in the past, most countries still face multiple obstacles when it comes to providing quality care. Expanding scientific knowledge in the region, integrating LATAM populations in clinical trials, establishing MS care units, enhancing access to MS diagnosis and tools, and ensuring accessibility to DMTs and symptomatic treatments are some of the main challenges health care providers must address in the coming years.

Multiple Sclerosis Care in Latin America

Inpatient rehabilitation improves health-related quality of life (HRQOL) for people with multiple sclerosis (MS). However, the obtained improvements decline once people return home. The challenge is to find ways to preserve the beneficial effects for the long term. We investigated whether monthly telecoaching after discharge would enhance the long-term carryover of improvements.

We conducted a 1-year exploratory study with 2 delivery methods: telephone coaching and web-based coaching. After discharge, the telephone group received monthly calls; the web-based group responded to monthly online coaching questions. Based on their rehabilitation goals, we put patients into a neuropsychological group or a physical group. In addition, we matched each patient with similar wait-list control patients and treatment patients from the main study. The primary outcome was HRQOL measured by the Functional Assessment in Multiple Sclerosis (FAMS).

The neuropsychological group had long-term preservation of HRQOL with both delivery methods, with telephone coaching seeming to be superior. Mean differences in FAMS at the 12-month median follow-up for the neuropsychological group compared with the control wait-list control group were for the telephone group: + 15.4 (95% CI, 3.5-27.4; P = .011); for the web-based group: + 10.9 (95% CI, −3.3 to 25.2; P = .130); for the control treatment group: + 6.9 (95% CI, 0.6-13.3; P = .031). The physical group saw no beneficial effects from telecoaching.

Following inpatient multidisciplinary rehabilitation, monthly telecoaching of individuals with MS with neuropsychological challenges enhanced the long-term carryover of HRQOL, with one-on-one telephone coaching showing more pronounced improvements than web-based automated coaching.

From The Danish MS Hospitals, Ry and Haslev, Denmark (MN, FB, AGS, EJ, JH); Aarhus University Hospital, Aarhus, Denmark (PVR); University of Southern Denmark, Denmark (TP); Danish Technological Institute, Aarhus, Denmark (PT). 

: Michael Nørgaard, MSc, The Danish MS Hospitals, Ringstedvej 106, 4690 Haslev, Denmark; 

 The authors declare no conflicts of interest.

 The study was a poster at the Consortium of Multiple Sclerosis Centers Annual Meeting; June 1, 2023; Denver, Colorado. It was also an oral presentation at the European Committee for Treatment and Research in Multiple Sclerosis/Rehabilitation in Multiple Sclerosis Annual Meeting; October 29, 2022; Amsterdam, the Netherlands.

 (MDR) seeks to optimize functional status and, ultimately, improve health-related quality of life (HRQOL) by building self-efficacy and self-management.

 It is gradually becoming well documented that MDR, especially inpatient MDR, is effective in giving people with multiple sclerosis (MS) the tools, strategies, and support they need to significantly improve their HRQOL.

 After discharge, however, they must reintegrate into the community and implement the skills and knowledge about managing daily life with MS at home. MDR rehabilitation plans often include recommendations for a range of additional community services after discharge. However, the community-based support system is often not strong enough to support patients sufficiently, and that limits the long-term benefits of inpatient rehabilitation.

 Without the necessary aftercare support from rehabilitation professionals, motivation and, subsequently, the acquired skills and tools are lost, causing a decline in HRQOL.

 The few longitudinal studies on MDR in MS show that the HRQOL improvements from an inpatient stay decline by approximately half 6 to 12 months after patients have returned home.

 The challenge is to find ways to preserve the beneficial effects by bridging the gap between inpatient MDR and community return.

Previous research suggests that extended outpatient or home-based MDR may be a solution,

 but an emerging method is telerehabilitation, either synchronous (eg, telephone- or video-based) or asynchronous (eg, automated web-based or virtual reality). It has the potential to be a more cost-effective alternative to periodic outpatient or home visits or admissions to resource-intensive inpatient MDR. Unfortunately, there is limited evidence on the efficacy of telerehabilitation in improving HRQOL in people with MS.

 At the onset of the present study, there was some evidence of stand-alone phone-based or web-based self-management interventions for physical activity,

 Surveys had also revealed high interest among individuals with MS in telecommunication for health care services.

 Investigators in a Dutch long-term study explored telecounseling after discharge from physical rehabilitation in a large group of patients, including some with MS, and found promising results on physical activity from 3 telephone counseling sessions that were 2 to 3 weeks apart.

 However, no previous inpatient MDR studies had monitored the benefits of regular, after-discharge telecoaching to support self-management and HRQOL in individuals with MS.

Based on this background data, we set out to investigate whether monthly telecoaching for individuals with MS after 4 weeks of inpatient MDR would enhance the long-term carryover of improvements in HRQOL.

We conducted an exploratory 2-group intervention study with 6- and 12-month follow-up (MFU) based on a protocol amendment (in Danish and unpublished) to the main protocol of The Danish MS Hospitals Rehabilitation Study.

 Initially, patients were admitted to 4 weeks of inpatient MDR in accordance with the main protocol. The protocol amendment added monthly coaching after discharge. The included patients were allocated to receive 1 of 2 different types of telecoaching after discharge: telephone coaching (20 patients) or web-based coaching (20 patients). The web-based content was exclusively text-only.

The study was approved by the Danish Research Ethics Committee (ref. no. 1-01-83-0002-07) and the Danish Data Agency (ref. no. 2011-41-6751). It was registered at isrctn.com (ISRCTN05245917). For further details of the study, please see the first report(s).

Recruitment took place in August and September 2014. All referred participants were aged 18 to 65 years and had an Expanded Disability Status Scale (EDSS) score equal to or less than 7.5. Exclusion criteria were as follows: people with MS who were within 3 months of relapse, who were within 6 months of diagnosis, who had participated in inpatient MDR in the previous 6 months, who had an EDSS cognition subscale score less than 2, or who had cognitive limitations or any other illness that could impede their participation in the study. All participants underwent full neurological examinations prior to enrollment in the study. The examining neurologists made the final decision on the patients’ enrollment. Informed consent was obtained from all participants.

Prior to admission, participants had a one-on-one goal-setting conversation with their case manager to make a joint decision about functional rehabilitation goals.

 Based on the nature of their goals, they were assigned to the most appropriate of the 5 main focus areas (MFAs): resilience, cognitive function, energy, physical function, and personal needs. MDR included a patient-centered, collaborative, and goal-oriented team-based approach involving neurologists, nursing staff, physiotherapists, occupational therapists, social workers, dietitians, neuropsychologists, and psychologists. The MDR program offered during admission has been previously described.

The first 20 consecutive eligible participants were enrolled in the telephone group, and the next 20 were enrolled in the web-based group. Blinding of participants’ identifying information to the MS specialists was not possible. Different measures were taken to counteract this limitation. For example, only the case managers were directly informed about the participants’ group assignments, and participants were urged not to discuss their groups with the MS specialists. No distinction was made among the study, wait-list, and control patients. Finally, the outcome measure was self-reported and completed at home online

 to avoid any influence from the MS specialists and researchers.

The total cohort was 40 participants. Of the 20 in the telephone group, 8 were assigned to the MFA of energy, 5 to cognitive function, 5 to resilience, and 2 to physical function. Of the 20 in the web-based group, 5 were assigned to energy, 2 to cognitive function, 5 to resilience, and 8 to physical function. Patients in the telephone group tended to be younger than patients in the web-based group (median of 49 years vs 56 years). Otherwise, the groups looked much the same at study start. The baseline demographics of patients with neuropsychological MFAs (resilience, cognitive function, and energy) and patients with physical function as their MFA are given in 

, along with disease characteristics. The median length of stay was 20 days (range, 14-20 days). No patients dropped out of the study, and all participants completed the 1-year follow-up. All were stable during the study period, with no overall progression in EDSS and no major changes in use of immunotherapy.

The primary outcome was MS-specific HRQOL assessed by the self-administered Functional Assessment in Multiple Sclerosis (FAMS).

 FAMS consists of 44 questions (items) divided into 6 multi-item functional status scales: mobility (7 items), symptoms (7 items), emotional well-being (7 items), general content (7 items), thinking/fatigue (9 items), and family/social well-being (7 items). Each item is rated on a 5-point Likert scale (0-4), yielding a possible score range of 0 to 176. Higher scores reflect better functional status and higher HRQOL.

The intervention consisted of structured coaching sessions focusing on goal attainment delivered via telephone or the internet. Sessions were scheduled once a month for 11 months beginning 1 month from discharge. The case managers (ie, MS nurse, physiotherapist, or occupational therapist) were all certified coaches, and they conducted the telephone coaching sessions and monitored the automated online coaching sessions, ready to act if necessary. During the study, case managers recorded completed sessions as well as the number and duration of telephone calls for both groups. For every patient, the case manager was the single point of contact. Support was available upon request from the case manager either by telephone or email in case of technical problems or personal concerns. Case managers made referrals to general practitioners or neurologists in situations of relapses, health evaluations, and medication reviews.

The typical telephone coaching session involved open-ended questions to facilitate conversation about progress toward goal achievement, adherence to the rehabilitation program, identification of new issues, strategies to overcome barriers, and long-term planning. If a participant did not attend the session, the case manager tried to connect by calling in the following 2 days or by sending an email.

Using a device of their choice, web-group participants responded to standardized closed-ended coaching questions to facilitate reflections on goal achievements. The ODD software system, developed and supported by the now-closed company OVAM ApS, was used for these sessions. The ODD system automatically notified the patients of upcoming sessions via email. Automatic reminders were sent to participants via email if they did not log on within 2 days and if they did not respond, the case manager telephoned. At each session, the patient’s personal rehabilitation goal was highlighted at the top of the screen.

How active are you in relation to the goal you have set up?

(Not at all) to 10 (Very active every day)

How close are you to your goal right now?

(Far from the goal) to 10 (The goal has been achieved)

How important is your goal to you right now?

(Not important at all) to 10 (Very important)

Each of these was followed by a feedback question to promote reflection. The feedback questions were:

If the response to the corresponding main question was a reduction equal to or greater than 2 points: Your score is lower than your previous score. What do you have to do to turn the tide?

If the response to the corresponding main question was plus or minus 1 point: Your score is about the same as your previous score. What do you have to do to improve your result?

If the response to the corresponding main question was an increase equal to or greater than 2 points: Your score is better than your previous score. What did you do and what did you learn from your good results?

An email alert was sent to the case manager if the answer to 1 of the main questions was between 0 and 3, or if the response was a negative change of 3 or more to 1 of the main questions. The case manager then contacted the patient to assist. Case managers were instructed to keep the extent and duration of the telephone counseling to an absolute minimum in such cases.

To establish a controlled analysis against the main study, each participant in the present study was matched with a similar wait-list control participant and treatment participant from the main study,

 thereby comparing both intervention groups with the 2 newly established matched control groups: control wait-list patients and control treatment patients. To control for confounder imbalances, we used 1-to-many caliper matching without replacement within the 2-dimensional Euclidean space defined by the first 2 components of a joint correspondence analysis carried out on baseline demographic, clinical, and HRQOL variables and MFA. We chose this multivariate matching strategy because the clinical and HRQOL variables were previously reported to be highly associated.

 Statistical analyses followed Trénel et al.

 Participants in the neuropsychological MFAs (ie, resilience, cognitive function, and energy) were combined into 1 group in the outcome measure analysis to increase statistical power and, thus, all participants were divided into either neuropsychological or physical (physical function) groups. All analyses were performed using R (www.r-project.org).

The multivariate retrospective matching yielded a total of 33 match groups consisting of between 2 and 12 participants (median = 7). A total of 224 patients in the matched data were distributed into 4 groups: telephone group (n = 19; 1 patient was isolated in the joint control analysis and, hence, excluded from the main analysis), web-based group (n = 20), control treatment group from the main study (n = 95), and control wait-list control group from the main study (n = 90). All patients were assigned to a single match group (no replacement), with patients always assigned to the smallest possible match group to improve match group size balance. Because the match control treatment patients and the wait-list control patients originated from the main study, the present case managers had no knowledge of and no interactions with these match patients.

Overall adherence with the coaching intervention was 100%. The case managers successfully completed the planned 1-year follow-up sessions for all patients. In the 11 months after discharge, every patient was coached on 9 occasions. The telephone group had 180 coaching sessions in total with a mean duration of 25 minutes (range, 5-90 min). Mean duration of sessions was longest at the first scheduled session (32 min) and shortest at the sixth session (19 min). The web-based group had 33 unplanned telephone conversations with a mean duration of 13 minutes (range, 5-40 min). The number of telephone conversations peaked at the first scheduled session with 10 out of 20 patients in need of telephone counseling. It then dropped gradually during the first half of the study period to only 1 or 2 telephone calls at each scheduled web-based coaching session in the second half of the study. Mean duration of unplanned telephone calls in the web-based group was longest at the third scheduled session (20 min; average of 5 telephone conversations), and shortest at the second session (11 min; average of 7 telephone conversations). According to the case managers, a majority of the unplanned telephone calls were about technical issues and not because of clinical needs. Internal semistructured focus group interviews after the end of the study revealed high satisfaction with both telecoaching interventions.

Baseline values as well as changes and differences in HRQOL during the study period are presented in 

. As shown, the adjusted baseline FAMS scores looked similar between the groups. This suggests that the matching method successfully controlled for any confounder imbalances. However, significant within-group increases in mean FAMS scores were found in all groups at discharge, indicating substantial improvements in HRQOL from inpatient MDR.

In the neuropsychological group patients, both telecoaching groups demonstrated sustained improvements in HRQOL throughout the study period when compared with the control patients, with telephone coaching being superior. In the telephone group, a major additional HRQOL improvement was seen from 6-MFU to 12-MFU. With the control wait-list control group as reference, mean differences in FAMS scores at 12-MFU compared with baseline were: telephone group +15.4 (95% CI, 3.5-27.4; P = .011), web-based group + 10.9 (95% CI, −3.3 to 25.1; P = .130), and control treatment group + 6.9 (95% CI, 0.6-13.3; P = .031). In contrast, the physical group patients had no beneficial effects from either telephone coaching or web-based coaching: the gains seen at discharge were lost during the study period.

The present explorative study finds that systematic coaching in the form of one-on-one calls for individuals with MS with neuropsychological rehabilitation goals seemed to improve the long-term carryover of HRQOL improvements gained during inpatient MDR. However, due to the very low number of physical patients assigned to telephone coaching, we cannot draw any conclusions about this subgroup based on the present results.

We learned from the main study that the patients assigned to the resilience, cognitive function, and energy MFA groups shared similar neuropsychological challenges and also had comparable long-term improvements in HRQOL from inpatient MDR.

 Thus, we felt confident in combining the 3 groups in this analysis to increase statistical power. Despite a clear decline from discharge, continued improvements were seen for both telecoaching methods for the neuropsychological group at 6-MFU and 12-MFU when compared with the control groups. Telephone coaching seemed to be especially beneficial in the long term, with additional improvement in HRQOL from 6 to 12 months, almost reaching discharge values. This almost doubled the long-term benefits when compared to control treatment patients from the main study, who were not offered telecoaching after discharge.

Adding monthly telephone coaching after discharge changed the curve and largely prevented the expected decline in HRQOL for individuals with MS in the neuropsychological group compared with other longitudinal inpatient MDR studies.

 This suggests that the more comprehensive reevaluation and support for self-management in the personal one-on-one coaching in the telephone group made a significant difference and provided a basis for a solid long-term improvement in HRQOL. The delayed additional improvement in HRQOL in the neuropsychological telephone coaching group indicated that despite the advantage of the one-on-one coaching, community reintegration required time to transfer the acquired knowledge and tools for managing daily life with MS to the home environment. It is also possible the personal relationships between the patients and the case managers that were maintained through the regular telephone calls contributed to the favorable outcome. We know from surveys that interpersonal relationships are very important components of effective rehabilitation.

 We chose telephone coaching because we are familiar with this type of telesupport in our daily clinical practice; telephone administration has also proven to be effective for individuals with MS in other rehabilitation studies.

 Web-based coaching was included as a novel, less expensive, and less extensive alternative.

The present results are in line with the findings of Flachenecker et al, who have been the only ones to report the benefits of telephone-/web-based coaching for individuals with MS after inpatient rehabilitation.

 They conducted their study at the same time as ours and, despite the fact that their primary objective was physical activity, they found that postdischarge coaching maintained improvements in HRQOL throughout the study period of 6 months, a time point where no support had been given for 3 months. That is impressive, but may also explain why they found no indication of additional improvements in HRQOL over time, as we did. In our study, the closed-ended web-based coaching questions were insufficient to support the HRQOL improvements gained from the stay in the physical group patients. In our experience, more so than neuropsychological patients, physical rehabilitation patients face more challenges such as a sedentary lifestyle and the task of incorporating the physical activities of MDR into daily life. The physical group patients needed more comprehensive aftercare support and would probably have benefited from personal one-on-one coaching with a case manager, as was the case with the neuropsychological patients. Unfortunately, this study is unable to answer that question.

Previous research has found it difficult to prove the benefits of teleinterventions on HRQOL.

 Therefore, it is promising that our results support recent teleintervention studies, including the work of Flachenecker et al, showing that it is possible to support and improve the HRQOL of people with MS over time with home-based telecoaching/counseling, and also after inpatient rehabilitation.

Long-term preservation of HRQOL in chronic degenerative diseases such as MS should be considered a marker of therapeutic success.

 Individuals with MS in general have decreasing HRQOL

 and a recent study found that additional worsening of HRQOL predicts progression of disability.

 Given the progressive nature of MS and the unpredictable issues individuals with MS may face down the road, it is not sufficient to have an appointment with a rehabilitation professional occasionally.

 If our long-term aim is to continuously support self-management in order to optimize mental and physical capacity and maintain HRQOL in people with MS, regular reviews by MS rehabilitation specialists are necessary.

 Rehabilitation experts have proposed that individuals with MS would benefit from a personal coach who supports and gives advice when needed,

 although the long-term effectiveness of coaching in rehabilitation has been unclear.

 Our results suggest that continuous one-on-one coaching of individuals with MS has substantial long-term potential in combination with inpatient MDR.

This study was limited by small sample sizes and the lack of a genuine control group. Also, the present study was never designed to stratify patients based on MFA, which regrettably resulted in a skewed distribution with a strong preponderance of neuropsychological participants in the telephone group and only 2 participants assigned to physical function. Thus, interpretation of these data should be made with some caution.

Integration of various telerehabilitation interventions to extend the carryover effects on HRQOL after MDR calls for further high-quality, long-term effectiveness studies of both current and rising technologies.

This study provides preliminary evidence that monthly telecoaching of individuals with MS with neuropsychological rehabilitation goals enhances the long-term carryover of improvements in HRQOL from inpatient MDR. Overall effects seemed more pronounced using a synchronous intervention (telephone coaching) vs an asynchronous intervention (web-based coaching).

Telecoaching of Individuals With Multiple Sclerosis After Inpatient Multidisciplinary Rehabilitation: The Danish MS Hospitals Rehabilitation Study

Exercise is effective for managing symptoms and improving quality of life among people with multiple sclerosis (MS). However, African Americans are underrepresented in MS exercise trials, partly due to limited recruitment resources and avenues tailored to this demographic. This paper describes participant outreach and recruitment strategies for an ongoing, remotely delivered, culturally tailored exercise training program for African American individuals with MS.

Initially, a passive, indirect approach in the form of virtual outreach was employed, distributing study information through MS organizations, local experts, community leaders, patient representatives, and others in the southern United States. The effectiveness of these outreach and recruitment strategies in screening and enrolling was assessed using study coordinator and participant data.

Over 15 months, the outreach methods successfully recruited 80 African Americans with MS into the clinical trial. Following a delayed start and slower initial recruitment, active outreach strategies were incorporated (eg, in-person engagements at local MS events, recreation and community centers, health care facilities, and schools). Additional tactics included study website enhancements, an informational video, email templates, and updates to the study flyer. Most participants (64.9%) were recruited through MS organizations, with virtual platforms (ie, websites, social media; 14.3%) and support groups (9.1%) also contributing to recruitment success.

This study demonstrates the effectiveness of a multipronged, experience-informed approach for successfully enrolling African Americans with MS into clinical trials. While MS organizations proved pivotal for recruiting and enrolling African Americans with MS, leveraging diverse recruitment outlets highlighted the importance of multifaceted strategies for engaging participants from minority backgrounds in research.

From the Department of Health Behavior, The University of Alabama at Birmingham, Birmingham, AL (WNN DP); Department of Kinesiology and Nutrition, The University of Illinois at Chicago, Chicago, IL (DG, VF, RWM); NORC at the University of Chicago, Chicago, IL (EF); Joi Life Wellness Group Multiple Sclerosis Center, Atlanta, GA (MJW); and the School of Kinesiology, University of Michigan, Ann Arbor, MI (DK-H). 

Whitney N. Neal, Department of Medicine, The University of Alabama at Birmingham, 1717 11th Ave S, Birmingham, AL, 35205; 

: wneal@uabmc.edu. Robert W. Motl, PhD, Department of Kinesiology and Nutrition, The University of Illinois at Chicago, 1919 West Taylor St, Chicago, IL, 60612; 

The authors declare no conflicts of interest.

This research is funded through a grant from the Bristol Myers Squibb Foundation (BMSF). All statements in this paper reflect those of the authors and do not necessarily reflect the views of the BMSF.

 The study design and preliminary data from the clinical trial were presented as an oral presentation at the Consortium of Multiple Sclerosis Centers Annual Meeting; May 29-June 1, 2024; Nashville, Tennessee.

Exercise training is highly effective for managing symptoms and improving health-related quality of life among persons with multiple sclerosis (MS),

 yet African American (AA) individuals with MS report lower levels of physical activity participation than White individuals.

 This may, in part, be associated with the observation that the majority of exercise training randomized controlled trials (RCTs) involving people with MS lack information on the race or ethnicity of participants (n = 44, 81%), and in the 9 studies that did collect those data, only 1.7% of participants self-identified as AA.

 There is an absence of evidence of the benefits of exercise training, and rehabilitation broadly, in AA individuals with MS, thereby undermining efforts for behavior change and health promotion.

One potential reason for the limited recruitment and inclusion of diverse samples of people with MS in exercise training RCTs may be that recruitment has often been achieved through a single avenue, typically an MS specialty clinic (84.7%) or an MS organization (13.2%).

 These avenues increase confidence that the people recruited will meet necessary diagnostic criteria for MS, but they may result in limited minority representation based on inequitable health care access across racial and ethnic groups. One review reported that AA and Hispanic people with neurological illnesses, including MS, were less likely to access outpatient neurological care and more likely to seek care in the emergency department compared with their White counterparts.

 Another study observed that AA participants were more likely to cite newspapers or magazines and others with MS as trustworthy sources of research information and less likely to trust universities compared with White participants.

 This suggests that relying on recruitment through MS clinics and organizations alone may impact the diversity of resulting samples.

Effective recruitment of AA participants with MS may require multipronged, nontraditional avenues such as collaboration with nonspecialist community providers and local agencies.

 We are aware of 2 papers involving exercise interventions for people with MS that provide detailed data on multipronged recruitment strategies.

 The papers highlight the use of consultant mail-outs, engagement of clinical partners, and trial awareness strategies; however, neither study described specific strategies for the inclusion of participants from underrepresented groups or included data on the race or ethnicity of the enrolled participants.

To facilitate recruitment of AA individuals with MS into exercise training RCTs, and perhaps rehabilitation more broadly, the field requires greater awareness of the unique needs and preferences of the target population. This paper describes our experiences and lessons learned with outreach and recruitment strategies implemented in an ongoing RCT of a remotely delivered, culturally tailored exercise training program for AA persons with MS.

 We also report on the strategies that were most effective in screening and enrolling participants. These strategies may help future researchers recruit participants with MS from underrepresented populations into RCTs of exercise training and, perhaps, other rehabilitation research.

The Targeted Exercise for African-Americans with MS (TEAAMS) study examines the effects of a 16-week, remotely delivered, culturally tailored aerobic and resistance exercise training program compared with an active control condition (stretching and flexibility) for immediate and sustained improvements in walking and other outcomes among AA persons with MS located in the southern portion of the US. The primary outcomes are walking dysfunction, as measured by the Multiple Sclerosis Walking Scale (MSWS-12), and mobility disability based on the Patient-Determined Disease Steps (PDDS). Outcomes are assessed remotely via Qualtrics at baseline, immediately post intervention (4 months), and 4 months post intervention (8 months). The University of Illinois at Chicago (UIC) Institutional Review Board approved this study, and all participants provided informed consent before enrollment. The TEAAMS study protocol has been described fully elsewhere.

All participants were screened by the project coordinators (E.F. and D.G.) before entering the trial. The primary criteria for inclusion and exclusion are included in 

. Participants who satisfy the initial eligibility assessment complete a second screening on walking dysfunction (MSWS-12 score of 25-75 on a 100-point scale) and mobility disability (PDDS score of 2-6 on an 8-point scale).

The power analysis indicated enrollment of 80 participants (40 per group) to yield appropriate power for testing the time × condition interaction on the main trial outcome of walking impairment. The final enrollment goal is 100 participants (50 per group) based on an anticipated dropout rate of approximately 20%. The project is funded for 4 years, and the initial enrollment target was 5 participants per month over 20 months, with recruitment beginning in November 2022.

The sociocultural and historical factors surrounding the recruitment of underrepresented groups mentioned in the introduction influenced decisions about staffing, collaborators for recruitment efforts, and recruitment strategies. We began planning recruitment activities in July 2022 during a team meeting. The meeting included the study principal investigator (White male, Illinois resident) and co-investigator (White female, Alabama resident), project coordinator (Hispanic/Latino male, Illinois resident), outreach coordinator (Black female, Alabama resident), consultant (Black female, Michigan resident), and behavioral coach (Filipino female, Illinois resident). The principal investigator (PI; R.W.M.) described the purpose of the study, its eligibility requirements, and preliminary plans for recruitment (eg, development of a study name and logo). The group then brainstormed potential recruitment strategies and sources and discussed the rationale of our recruitment strategy (ie, existing health inequities among AA individuals with MS living in the southeast) and the logistics of virtual recruitment and outreach. We decided that study outreach activities to support participant recruitment would be performed by the University of Alabama at Birmingham (UAB) outreach coordinator (W.N.N.), under the supervision of the UAB-site PI (D.P.). The UIC would play a passive role in outreach and oversee participant screening, consenting, data collection, participant monitoring, intervention delivery, and data analysis and interpretation.

The initial and subsequent team meetings allowed for the development of an explicit marketing plan, discussion of logistics for participant screening and enrollment, and identification of additional recruitment sources, strategies, and methods. Participants would be recruited in groups or waves staggered at 4-month intervals, with the first wave of participants beginning the intervention in December 2022 and assessments for the final wave planned for November 2024. We aimed to screen 30 to 40 participants per wave and enroll 20 participants per wave for our sample size goal of 100 participants in 20 months.

Description of Our Original Outreach and Recruitment Strategy

Our outreach and recruitment strategy considered participant-level barriers for diverse populations, including lack of access to competent care, lack of awareness of clinical trial opportunities, mistrust, and systemic racism and discrimination. Because previous research suggests that AA individuals with MS are less likely to trust universities as sources of research information,

 the lead outreach coordinator did not share study information directly with AA individuals with MS. Instead, the original plan focused on a passive, indirect approach to recruitment in the form of virtual outreach to MS organizations, local experts in the disease area, trusted community leaders, and patient advocates. We anticipated initiating outreach and recruitment efforts one state at a time, starting with Alabama. See 

for an overview of the original recruitment strategy.

To ensure recognition of the TEAAMS study, a logo (

) was developed to be included on all study materials for project branding and recognition. We created a study website to provide a brief overview of the study, eligibility information, and contact details for the study team (https://projectteaams.ahs .uic.edu/). Program materials were modified to include culturally appropriate content based on formative feedback from a national sample of AA individuals with MS.

 The modifications included (1) images of AAs in the program manual, newsletters, and videos; (2) resources and tips that address culturally relevant barriers to exercise; and (3) inspirational quotes rooted in faith and/or well-known quotes.

Modifications of the Original Recruitment Strategy

We anticipated that most individuals would be recruited through the methods described in Table 1, yet regular engagement among the research team, feedback from trusted community leaders and patient advocates, and trial-and-error provided opportunities to improve the scope and effectiveness of outreach efforts through modifications to the original recruitment strategy. The recruitment and enrollment period was extended from 20 to 22 months (November 2022 to September 2024) due to a delayed intervention start by 1 month and the initial recruitment rate being slower than expected. After the first wave of participants, we modified our recruitment and enrollment timeline (ie, enrollment staggered at 4-month intervals with 20 participants per wave) so that subsequent waves began at 2-month intervals with 6 to 10 participants per wave. Outreach and recruitment efforts were expanded to include all states per wave and targeted Southern states (ie, Alabama, Arkansas, Florida, Georgia, Kentucky, Louisiana, Mississippi, North Carolina, South Carolina, Tennessee, and Texas). After the initial months of recruitment, we shifted our focus from contacting churches and health ministries to partnering with other community organizations, such as public libraries; local and AA-owned newspapers; and AA civil, social, or fraternal organizations. Virtual, primarily passive, outreach efforts were broadened to include active strategies (eg, face-to-face engagement at local recreation or community centers, senior centers, health care facilities, schools, and community or health fairs).

Modifications to outreach and recruitment materials included: (1) creating a short video describing the study, which was provided to champions and change agents (eg, faith-based organizations, social media influencers, community organizations) for online sharing (see supplementary content); (2) updating email templates used to contact champions and change agents to increase response rates (eg, using lay language for support group leaders, defining MS for non–disease-specific organizations, personalizing to location, adding headshot to signature); (3) adding a prescreening form to the study website that allows interested individuals to be contacted by the study coordinator; and (4) revising the language on the study flyer to highlight the benefits of participating in the study and including a QR code to direct participants to the website and prescreening form (

As of February 2024, the outreach coordinators contacted 453 entities, including MS organizations, health care providers, community organizations, patient representatives, universities, and professional organizations. The response rates from the entities differed by category, with MS organizations (ie, National Multiple Sclerosis Society [NMSS], Multiple Sclerosis Association of America [MSAA], North American Research Committee on Multiple Sclerosis [NARCOMS], National African Americans with Multiple Sclerosis Registry [NAAMSR], Accelerated Cure Project [ACP], Multiple Sclerosis Views and News [MSV&N], and Multiple Sclerosis Foundation [MSF]) yielding the highest response rates. Those organizations supported our outreach efforts by sharing study information through emails, newsletters, and social media with registry members who met our basic eligibility criteria (ie, self-identify as Black or AA, live in 1 of the included states), or by providing direct access to self-help group leaders for further community outreach (MSF). Of the 24 directly contacted MSF self-help groups, 4 agreed to distribute study flyers, and 2 requested an information session. Both sessions were conducted via Zoom and included an introduction to general and MS-specific benefits of physical activity, recommendations for becoming and staying physically active, and an overview of the TEAAMS study, followed by a question-and-answer session. Additionally, the NMSS and MSV&N facilitated recruitment opportunities by inviting the lead outreach coordinator to local events (eg, fundraising walks, luncheons, and information sessions) to distribute TEAAMS study information. The NMSS also featured a blog post on their Momentum Magazine website describing how the TEAAMS study contributed to the need for more culturally competent research (https://www.nationalmssociety.org/news-and-magazine/momentum-magazine/research-and-science/breaking-the-cycle-of-exclusion). While few individually owned physical therapy clinics responded to our request to share study information with their clients, a partnership was established with a large physical therapy provider to distribute information to clinicians and patients at over 500 clinics throughout the South.

Of the 42 AA-owned newspapers contacted, one (

Recruitment of African American Adults With Multiple Sclerosis Into Randomized Controlled Trials of Exercise Training: Lessons Learned From Project TEAAMS

Jie Li, MD

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